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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: BMS-790052
* Drug: BMS-650032
* Drug: BMS-650032
* Drug: BMS-650032
* Drug: Pegylated-interferon alfa-2a
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Sentinel A<br>BMS-790052 (60mg) once daily + BMS-650032 (600 mg) twice daily | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 600 mg, twice daily, 24 weeks<br>|
| Experimental: Arm 2: Sentinel B<br>BMS-790052 (60mg) once daily + BMS-650032 (600mg) twice daily + Pegylated-interferon alfa-2a + Ribavirin | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 600 mg, twice daily, 24 weeks<br>Drug: Pegylated-interferon alfa-2a<br>* Syringe, Subcutaneous Injection, 180 µg, once weekly<br>* Other names: Pegasys;Drug: Ribavirin<br>* 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<br>* Other names: Copegus;|
| Experimental: Arm 3: Expansion A1<br>BMS-790052 (60mg) once daily + BMS-650032 (200mg) twice daily | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 200mg, twice daily, 24 weeks<br>|
| Experimental: Arm 4: Expansion A2<br>BMS-790052 (60mg) once daily + BMS-650032 (200mg) once daily | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 200 mg, once daily, 24 weeks<br>|
| Experimental: Arm 5: Expansion B1<br>BMS-790052 (60mg) once daily + BMS-650032 (200 mg) twice daily + Pegylated-interferon alfa-2a + Ribavirin | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 200mg, twice daily, 24 weeks<br>Drug: Pegylated-interferon alfa-2a<br>* Syringe, Subcutaneous Injection, 180 µg, once weekly<br>* Other names: Pegasys;Drug: Ribavirin<br>* 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<br>* Other names: Copegus;|
| Experimental: Arm 6: Expansion B2<br>BMS-790052 (60mg) once daily + BMS-650032 (200 mg) once daily + Pegylated-interferon alfa-2a + Ribavirin | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 200 mg, once daily, 24 weeks<br>Drug: Pegylated-interferon alfa-2a<br>* Syringe, Subcutaneous Injection, 180 µg, once weekly<br>* Other names: Pegasys;Drug: Ribavirin<br>* 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<br>* Other names: Copegus;|
| Experimental: Arm 7: Expansion B3<br>BMS-790052 (60 mg) once daily + BMS-650032 (200 mg) twice daily + Ribavirin | Drug: BMS-790052<br>* Tablets, Oral, 60 mg, once daily, 24 weeks<br>Drug: BMS-650032<br>* Tablets, Oral, 200mg, twice daily, 24 weeks<br>Drug: Ribavirin<br>* 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<br>* Other names: Copegus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |