Safety Study of Pegylated Interferon Lambda Plus Single or 2 Direct Antiviral Agents With Ribavirin

Study Overview
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Brief Summary
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The purpose of this study is to determine if combination therapy with Pegylated Interferon Lambda (BMS-914143) plus Ribavirin (RBV) with a single direct antiviral agent (BMS-790052 or BMS-650032) for 24 weeks is effective and safe for treatment of Chronic Hepatitis C (CHC) compared to current standard therapy with Pegylated Interferon Alpha-2a plus RBV for 48 weeks.

Detailed Description
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Study Classification: Pharmacokinetics/ Pharmacodynamics

Official Title
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A Phase 2B, Randomized Study to Evaluate the Safety and Efficacy of Pegylated Interferon Lambda (BMS-914143) Administered With Ribavirin Plus a Single Direct Antiviral Agent (BMS-790052 or BMS-650032) Versus Pegasys Administered With Ribavirin (Part A) and of Pegylated Interferon Lambda (BMS-914143) Administered With or Without Ribavirin Plus 2 Direct Antiviral Agents (BMS-790052 and BMS-650032) (Part B) in Chronic Hepatitis C Genotype-1 Treatment naïve Subjects

Conditions
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Hepatitis C

Intervention / Treatment
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* Biological: Pegylated Interferon Lambda (pegIFNλ)
* Drug: BMS-790052 (NS5A Inhibitor)
* Drug: Ribavirin (RBV)
* Drug: BMS-650032 (NS3 Protease Inhibitor)
* Biological: Pegylated Interferon Alfa-2a (pegIFNα-2a)
* Biological: Pegylated Interferon Lambda (pegIFNλ)
* Drug: Ribavirin (RBV)
* Biological: Pegylated Interferon Lambda (pegIFNλ)
* Drug: Ribavirin (RBV)
* Drug: BMS-790052 (NS5A Inhibitor)
* Drug: BMS-650032 (NS3 Protease Inhibitor)
* Drug: Placebo (PBO) for BMS-650032 (Placebo for NS3 Protease Inhibitor)
* Drug: Placebo (PBO) for BMS-790052 (Placebo for NS5A Inhibitor)
* Drug: Placebo for Ribavirin (RBV)
* Drug: Placebo for Ribavirin (RBV)


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com. Inclusion Criteria: Chronic Hepatitis C, Genotype 1 HCV RNA >100,000 IU/mL at screening; Seronegative for Human immunodeficiency virus (HIV) and Hepatitis B surface antigen (HBsAg); Liver biopsy within prior 2 years; subjects with compensated cirrhosis can enroll and will be capped at approximately 10% Exclusion Criteria: Any evidence of liver disease other than HCV; Co-infection with HIV; Diagnosed or suspected hepatocellular carcinoma; Medical history or laboratory value abnormalities that would prohibit the use of Pegylated Interferon Alpha-2a or Ribavirin

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1: pegIFNλ+BMS-790052+Placebo for BMS-650032+Ribavirin<br>Part A | Biological: Pegylated Interferon Lambda (pegIFNλ)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 24 or 48 weeks depending on response<br>* Other names: BMS-914143;Drug: BMS-790052 (NS5A Inhibitor)<br>* Tablets, Oral, 60 mg, Once daily, 24 weeks<br>* Other names: BMS-790052;Drug: Ribavirin (RBV)<br>* Tablets, Oral, 1000 or 1200 mg based on weight, Twice daily, 48 weeks<br>* Other names: Ribasphere;Drug: Placebo (PBO) for BMS-650032 (Placebo for NS3 Protease Inhibitor)<br>* Tablets, Oral, 0 mg, Twice daily, 24 weeks<br>* Other names: Placebo for BMS-650032;|
| Experimental: A2: pegIFNλ+BMS-650032+Placebo for BMS-790052+Ribavirin<br>Part A | Biological: Pegylated Interferon Lambda (pegIFNλ)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 24 or 48 weeks depending on response<br>* Other names: BMS-914143;Drug: Ribavirin (RBV)<br>* Tablets, Oral, 1000 or 1200 mg based on weight, Twice daily, 48 weeks<br>* Other names: Ribasphere;Drug: BMS-650032 (NS3 Protease Inhibitor)<br>* Tablets, Oral, 200 mg, Twice daily, 24 weeks<br>* Other names: BMS-650032;Drug: Placebo (PBO) for BMS-790052 (Placebo for NS5A Inhibitor)<br>* Tablets, Oral, 0 mg, Once daily, 24 weeks<br>* Other names: Placebo for BMS-790052;|
| Active Comparator: A3: pegIFNα-2a+PBO for BMS-790052+PBO for BMS-650032+RBV<br>Part A | Drug: Ribavirin (RBV)<br>* Tablets, Oral, 1000 or 1200 mg based on weight, Twice daily, 48 weeks<br>* Other names: Ribasphere;Biological: Pegylated Interferon Alfa-2a (pegIFNα-2a)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 48 weeks<br>* Other names: Pegasys®;Drug: Placebo (PBO) for BMS-650032 (Placebo for NS3 Protease Inhibitor)<br>* Tablets, Oral, 0 mg, Twice daily, 24 weeks<br>* Other names: Placebo for BMS-650032;Drug: Placebo (PBO) for BMS-790052 (Placebo for NS5A Inhibitor)<br>* Tablets, Oral, 0 mg, Once daily, 24 weeks<br>* Other names: Placebo for BMS-790052;|
| Experimental: A4: pegIFNλ+BMS-790052+BMS-650032+Ribavirin (24 weeks)<br>Part B | Drug: BMS-790052 (NS5A Inhibitor)<br>* Tablets, Oral, 60 mg, Once daily, 24 weeks<br>* Other names: BMS-790052;Drug: BMS-650032 (NS3 Protease Inhibitor)<br>* Tablets, Oral, 200 mg, Twice daily, 24 weeks<br>* Other names: BMS-650032;Biological: Pegylated Interferon Lambda (pegIFNλ)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 24 weeks<br>* Other names: BMS-914143;Drug: Ribavirin (RBV)<br>* Tablets, Oral, 1000 or 1200 mg based on weight, Twice daily, 24 weeks<br>* Other names: Ribasphere;|
| Experimental: A5: pegIFNλ+BMS-790052+BMS-650032+Ribavirin (16 weeks)<br>Part B | Biological: Pegylated Interferon Lambda (pegIFNλ)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 16 weeks<br>* Other names: BMS-914143;Drug: Ribavirin (RBV)<br>* Tablets, Oral, 1000 or 1200 mg based on weight, Twice daily, 16 weeks<br>* Other names: Ribasphere;Drug: BMS-790052 (NS5A Inhibitor)<br>* Tablets, Oral, 60 mg, Once daily, 16 weeks<br>* Other names: BMS-790052;Drug: BMS-650032 (NS3 Protease Inhibitor)<br>* Tablets, Oral, 200 mg, Twice daily, 16 weeks<br>* Other names: BMS-650032;|
| Experimental: A6: pegIFNλ+BMS-790052+BMS-650032+Placebo for RBV (24 weeks)<br>Part B | Drug: BMS-790052 (NS5A Inhibitor)<br>* Tablets, Oral, 60 mg, Once daily, 24 weeks<br>* Other names: BMS-790052;Drug: BMS-650032 (NS3 Protease Inhibitor)<br>* Tablets, Oral, 200 mg, Twice daily, 24 weeks<br>* Other names: BMS-650032;Biological: Pegylated Interferon Lambda (pegIFNλ)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 24 weeks<br>* Other names: BMS-914143;Drug: Placebo for Ribavirin (RBV)<br>* Tablets, Oral, 0 mg, Twice daily, 24 weeks<br>* Other names: Placebo for Ribasphere;|
| Experimental: A7: pegIFNλ+BMS-790052+BMS-650032+Placebo for RBV (16 weeks)<br>Part B | Biological: Pegylated Interferon Lambda (pegIFNλ)<br>* Solution, Subcutaneous, 180 μg/mL, Once weekly, 16 weeks<br>* Other names: BMS-914143;Drug: BMS-790052 (NS5A Inhibitor)<br>* Tablets, Oral, 60 mg, Once daily, 16 weeks<br>* Other names: BMS-790052;Drug: BMS-650032 (NS3 Protease Inhibitor)<br>* Tablets, Oral, 200 mg, Twice daily, 16 weeks<br>* Other names: BMS-650032;Drug: Placebo for Ribavirin (RBV)<br>* Tablets, Oral, 0 mg, Twice daily, 16 weeks<br>* Other names: Placebo for Ribasphere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability (as measured by the frequency of serious adverse events (SAEs), dose reductions and discontinuations due to adverse events (AEs) |  | Up to end of treatment ( maximum of 48 weeks) plus 30 days | 
| Antiviral activity as determined by the proportion of Hepatitis C virus (HCV) genotype 1 subjects with 24-week sustained virologic response (SVR24) |  | At end of treatment (maximum of 48 weeks) | 
| Antiviral activity as determined by the proportion of Hepatitis C virus (HCV) genotype 1 subjects with 24-week sustained virologic response (SVR24) |  | Post-treatment Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of HCV genotype 1 subjects with Protocol definition of virologic response (PDR) for Part A and Part B | Part A PDR is defined as HCV RNA at Week 4 < LLOQ and Week 12 undetectable Part B PDR is defined as HCV RNA at Week 2 ≥ 2 log10 decrease (or < Lower limit of quantitation (LLOQ) if baseline HCV RNA < 2400 IU/mL), Week 4 < LLOQ and Week 12 undetectable | Weeks 4, Weeks 12 and post-treatment Weeks 24 | 
| Proportion of subjects with either a 2-log or greater decrease in Hepatitis C virus (HCV) Ribonucleic acid (RNA) levels from baseline or undetectable levels of HCV RNA |  | Weeks 2, Weeks 4 and Weeks 12 | 
| Proportion of subjects with viral breakthrough, defined as confirmed > 1 log10 increase in HCV RNA over nadir or confirmed HCV RNA ≥ Lower limit of quantitation (LLOQ) after confirmed undetectable HCV RNA while on treatment |  | Post-treatment Week 48 | 
| Proportion of subjects with undetectable HCV RNA at the end of treatment that develop detectable levels of HCV RNA in the post-treatment follow-up period |  | Post-treatment Week 48 | 
| Serum HCV Ribonucleic acid (RNA) levels over time |  | Days 1, 3, Weeks 1, 2, 4, 6, 8, 12, 16, 20, and end of treatment (Week 16, 24 or 48 depending on treatment assignment) | 
| Proportion of subjects with undetectable HCV RNA over time |  | Days 1, 3, Weeks 1, 2, 4, 6, 8, 12, 16, 20, and end of treatment (Week 16, 24 or 48 depending on treatment assignment) | 
| Time to viral clearance, defined as an absence of detectable HCV RNA |  | Day 1, 3, Week 1, 2, 4, 6, 8, 12, 24, 36, end of treatment (Week 48), Post-Treatment at Week 4, 12, 24, 36, 48, and 56 | 
| Serum levels of pegIFNλ and pegIFNα-2a and plasma levels of BMS-790052 and BMS-650032: In PK sub-study group Maximum observed serum/plasma concentration (Cmax) |  | Cmax will be determined at Dose 5 (Study Visit Week 4: 0 - 12 h for BMS-650032, 0 - 24 h for BMS-790052, and 0 - 168 h for pegIFNλ and pegIFNα-2a) | 
| Serum levels of pegIFNλ and pegIFNα-2a and plasma levels of BMS-790052 and BMS-650032: In PK sub-study group Time to maximum concentration (Tmax) |  | Tmax will be determined at Dose 5 (Study Visit Week 4: 0 - 12 h for BMS-650032, 0 - 24 h for BMS-790052, and 0 - 168 h for pegIFNλ and pegIFNα-2a) | 
| Serum levels of pegIFNλ and pegIFNα-2a and plasma levels of BMS-790052 and BMS-650032: In PK sub-study group Minimal observed serum/plasma concentration (Cmin) |  | Cmin will be determined at Dose 5 (Study Visit Week 4: 0 - 12 h for BMS-650032, 0 - 24 h for BMS-790052, and 0 - 168 h for pegIFNλ and pegIFNα-2a) | 
| Serum levels of pegIFNλ and pegIFNα-2a and plasma levels of BMS-790052 and BMS-650032: In PK sub-study group Area under the serum/plasma concentration-time curve during one dose interval AUC(TAU) |  | AUC(TAU) will be determined at Dose 5 (Study Visit Week 4: 0 - 12 h for BMS-650032, 0 - 24 h for BMS-790052, and 0 - 168 h for pegIFNλ and pegIFNα-2a) | 
| Serum levels of pegIFNλ and pegIFNα-2a and plasma levels of BMS-790052 and BMS-650032: In all subjects, trough concentrations will be assessed (Ctrough) |  | Troughs at baseline (week 0), weeks 2, 4, 8, 12, 16, and 24 | 
| Proportion of subjects with 12-week sustained virologic response (SVR12), defined as undetectable HCV RNA |  | At end of treatment (maximum of 48 weeks) and follow-up Week 12 | 
| Proportion of subjects with 4-week sustained virologic response (SVR4), defined as undetectable HCV RNA |  | At end of treatment (maximum of 48 weeks) and follow-up Week 4 |