Phase III Hallmark QUAD: ASV+DCV+Peg+Rib (Nulls/Partials)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess efficacy, as determined by the proportion of subjects with Sustained Virologic Response at Post-Treatment Week 12 (SVR12), defined as Hepatitis C virus (HCV) Ribonucleic acid (RNA) < Limit of quantitation (LOQ) at post-treatment Week 12.

Detailed Description
-----------------
ASV = Asunaprevir (BMS-650032) DCV = Daclatasvir (BMS-790052) Peg = Peg-interferon Alfa-2a (PegIFN) Rib = Ribavirin (RBV)

Official Title
-----------------
A Phase 3, Open-Label Study With Asunaprevir and Daclatasvir Plus Peginterferon Alfa-2a (Pegasys) and Ribavirin (Copegus) (P/R) (QUAD) for Subjects Who Are Null or Partial Responders to Peginterferon Alfa 2a or 2b Plus Ribavirin With Chronic Hepatitis C Genotypes 1 or 4 Infection

Conditions
-----------------
Hepatitis C Virus

Intervention / Treatment
-----------------
* Drug: Asunaprevir
* Drug: Daclatasvir
* Drug: Peg-interferon Alfa-2a
* Drug: Ribavirin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females, ≥ 18 years of age HCV Genotype 1 or 4 who previously failed treatment with Peginterferon alfa-2a or peginterferon alfa-2b and Ribavirin (P/R), classified as previous null and partial responders based on previous therapy HCV RNA ≥ 10,000 IU/mL Seronegative for Human immunodeficiency virus (HIV) and Hepatitis B surface antigen (HBsAg) Subjects with compensated cirrhosis are permitted (compensated cirrhotics are capped at approximately 25% of treated population) Exclusion Criteria: Prior treatment of HCV with HCV direct acting antiviral (DAA) Evidence of a medical condition contributing to chronic liver disease other than HCV Evidence of decompensated liver disease including, but not limited to, a history or presence of ascites, bleeding varices, or hepatic encephalopathy Diagnosed or suspected hepatocellular carcinoma or other malignancies Uncontrolled diabetes or hypertension Total bilirubin ≥ 34 μmol/L (or ≥ 2 mg/dL) unless subject has a documented history of Gilbert's disease Alanine aminotransferase (ALT) ≥ 5x Upper limit of normal (ULN) Albumin < 3.5 g/dL (35 g/L) Alpha Fetoprotein (AFP) > 100 ng/mL (>82.6 IU/mL) or ≥ 50 and ≤ 100 ng/mL requires a liver ultrasound and subjects with findings suspicious of Hepatocellular carcinoma (HCC) are excluded Absolute neutrophil count (ANC) < 1.5 x 1000,000,000 cells/L (< 1.2 x 1000,000,000 cells/L for Black/African-Americans) Platelets < 90 x 1000,000,000 cells/L Hemoglobin < 12 g/dL for females or < 13 g/dL for males Any criteria that would exclude the subject from receiving P/R

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QUAD: Asunaprevir+Daclatasvir+Peg-interferon Alfa-2a+Ribavirin<br>Asunaprevir: Capsule, Oral, 100 mg, Twice daily, 24 weeks Daclatasvir: Tablet, Oral, 60 mg, Once daily, 24 weeks Peg-interferon Alfa-2a: Injection, subcutaneous (SC), 180 mcg/0.5 mL, Once weekly, 24 weeks Ribavirin: Tablet, Oral, 1000 mg/1200 mg (total daily dose), 24 weeks | Drug: Asunaprevir<br> <br> * Other names: BMS-650032;Drug: Daclatasvir<br> <br> * Other names: BMS-790052;Drug: Peg-interferon Alfa-2a<br> <br> * Other names: Pegasys®;Drug: Ribavirin<br> <br> * Other names: Copegus®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of genotype 1 subjects with SVR12, defined as HCV RNA < LOQ at post-treatment Week 12, for all subjects infected with HCV genotype 1 |  | At 12 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| On-treatment safety, as measured by frequency of Serious Adverse Events (SAEs) and discontinuations due to Adverse Events (AEs) through the end of treatment |  | Through the end of treatment (maximum up to 24 weeks) plus 7 days | 
| Proportion of subjects with SVR12 (HCV RNA < LOQ at post-treatment Week 12) by the rs12979860 single nucleotide polymorphisms (SNP) in the IL28 gene |  | At post-treatment Week 12 | 
| Proportion of subjects with HCV RNA undetectable |  | Weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12 [Extended rapid virologic response (eRVR)], end of treatment (up to 24 weeks), post-treatment Week 12 or post-treatment Week 24 | 
| Proportion of subjects with HCV RNA < LOQ |  | Weeks 1, 2, 4, 6, 8 and 12; at both Weeks 4 and 12, end of treatment (up to 24 weeks), post-treatment Week 24 (SVR24) | 
| Proportion of patients with SVR12 (HCV RNA < LOQ at post-treatment Week 12) for HCV genotype 4 subjects |  | Post-treatment Week 12 |