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

Study Overview
=================
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

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

Conditions
-----------------
Chronic Hepatitis C

Intervention / Treatment
-----------------
* Drug: BMS-650032
* Drug: BMS-790052
* Drug: BMS-791325
* Drug: Ribavirin


Participation Criteria
=================
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: 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 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: Documented Fibrotest score of ≤0.72 and aspartate transferase (transminase) to platelet ratio index (APRI) ≤2; OR Documented liver biopsy within 36 months preceding Day 1 showing absence of cirrhosis OR 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(75mg)<br>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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 2:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(75mg)<br>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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 3:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(150mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 4:BMS-650032(200 mg)+BMS-790052(60 mg)+BMS-791325(150mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 5:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 6:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 7:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 8:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group 9:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group10:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group11:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(75mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Group12:BMS-650032(200 mg)+BMS-790052(30 mg)+BMS-791325(150mg)<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> |
| Experimental: Grp13:BMS-650032(200mg)+BMS-790052(30mg)+BMS-791325(75mg)+RBV<br>* 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-650032<br> <br> * Other names: Asunaprevir (ASV);Drug: BMS-790052<br> <br> * Other names: Daclatasvir (DCV);Drug: BMS-791325<br> <br> Drug: Ribavirin<br> <br> * Other names: Copegus®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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) |