Study of Daclatasvir (BMS-790052) Add-on to Standard of Care in Treatment- naïve Patients

Study Overview
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Brief Summary
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To establish that at least 1 dose of daclatasvir combined with standard of care (pegylated interferon and ribavirin) is safe and well tolerated and demonstrates extended rapid virologic response rates at least 35% greater than those with placebo.

Official Title
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A Phase 2b Study of Daclatasvir in Combination With Peg-Interferon Alfa-2a and Ribavirin in Treatment Naive Subjects With Chronic Hepatitis C Genotype 1 and 4 Infection

Conditions
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Hepatitis C Virus

Intervention / Treatment
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* Drug: Daclatasvir
* Drug: Daclatasvir
* Drug: Placebo
* Drug: peg-interferon alfa-2a
* Drug: ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients chronically infected with hepatitis C virus (HCV) genotype 1 or 4 HCV RNA viral load of ≥100,000 IU/mL No previous exposure to interferon, pegIFNα, or RBV Results of a liver biopsy demonstrating absence of cirrhosis obtained ≤24 months prior to randomization. Compensated cirrhotics with Hepatitis C virus genotype 1 infection are eligible, but will be capped at 10% of the randomized study population (biopsy can be from any time period prior to randomization) Findings on ultrasound, computed tomography scan, or magnetic resonance imaging 12 months prior to randomization that do not demonstrate evidence of hepatocellular carcinoma Body mass index of 18 to 35 kg/m^2 Exclusion Criteria: Positive for hepatitis B or HIV-1/HIV-2 antibody at screening Evidence of a medical condition associated with chronic liver disease other than HCV Evidence of decompensated cirrhosis based on radiologic criteria or biopsy

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: Daclatasvir plus peg-interferon alfa-2a and ribavirin (20 mg)<br> | Drug: Daclatasvir<br>* Tablets, oral, 20 mg, once daily, 12-24 weeks, depending on response<br>Drug: peg-interferon alfa-2a<br>* Syringe, subcutaneous Injection, 180 µg, once weekly, 24 or 48 weeks depending on response<br>* Other names: Pegasys;Drug: ribavirin<br>* Tablets, oral, 1000 or 1200 mg based on weight, once daily, 24 or 48 weeks depending on response<br>* Other names: Copegus;|
| Experimental: Daclatasvir plus peg-interferon alfa-2a and ribavirin (60 mg)<br> | Drug: Daclatasvir<br>* Tablets, oral, 60 mg, once daily, 12-24 weeks, depending on response<br>Drug: peg-interferon alfa-2a<br>* Syringe, subcutaneous Injection, 180 µg, once weekly, 24 or 48 weeks depending on response<br>* Other names: Pegasys;Drug: ribavirin<br>* Tablets, oral, 1000 or 1200 mg based on weight, once daily, 24 or 48 weeks depending on response<br>* Other names: Copegus;|
| Placebo Comparator: Placebo plus peg-interferon alfa-2a and ribavirin<br> | Drug: Placebo<br>* Tablets, oral, 0 mg, once daily, 24 weeks<br>Drug: peg-interferon alfa-2a<br>* Syringe, subcutaneous Injection, 180 µg, once weekly, 24 or 48 weeks depending on response<br>* Other names: Pegasys;Drug: ribavirin<br>* Tablets, oral, 1000 or 1200 mg based on weight, once daily, 24 or 48 weeks depending on response<br>* Other names: Copegus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Extended Rapid Virologic Response (eRVR) | eRVR was defined as HCV RNA <lower limit of quantitation and target not detected at both Weeks 4 and 12 on treatment. | Weeks 4 and 12 | 
| Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Sustained Virologic Response (SVR24) | SVR24 was defined as HCV <lower limit of quantitation (LLOQ) and target not detected (TND) at follow-up Week 24. The LLOQ was 25 IU/mL, and <LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | Follow-up Week 24 | 
| Number of Participants With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), and Who Died | SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization. | From start of study treatment (day 1) up to follow-up Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Rapid Virologic Response (RVR) | RVR was defined as undetectable RNA (HCV RNA <lower limit of quantitation [LLOQ], target not detected [TND]) at Week 4. The LLOQ was 25 IU/mL, and <LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome. | Week 4 | 
| Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With Complete Early Virologic Response (cEVR) | cEVR was defined as undetectable RNA (HCV RNA <lower limit of quantitation [LLOQ], target not detected [TND]) at Week 12. The LLOQ was 25 IU/mL, and <LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome. | Week 12 | 
| Percentage of Hepatitis C Virus (HCV) Genotype 1 Participants With 12-week Sustained Virologic Response (SVR12) | SVR12 was defined as undetectable RNA (HCV RNA < lower limit of quantitation (LLOQ), target not detected (TND) at follow-up Week 12. The LLOQ was 25 IU/mL, and <LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome. | Follow-up Week 12 | 
| Percentage of Resistant Variants Associated With Virologic Failure | Virologic failure was defined as: Virologic breakthrough: confirmed >1 log10 increase in hepatitis C virus (HCV) RNA over nadir or confirmed RNA ≥lower limit of quantitation (LLOQ) after confirmed HCV RNA <LLOQ, target not detected (TND) while on treatment <1 log10 decrease in HCV RNA from baseline at Week 4 of treatment Failure to achieve early virologic response: <2 log10 decrease in HCV RNA from baseline and HCV RNA ≥LLOQ at Week 12 of treatment HCV RNA < LLOQ, TD or ≥ LLOQ at Week 12 and ≥ LLOQ at Week 24 HCV RNA ≥LLOQ or <LLOQ, target detected (TD) at the end of treatment (EOT) (including early discontinuation) Relapse, defined as HCV RNA ≥LLOQ or <LLOQ, TD during follow-up, after HCV RNA < LLOQ, TND at EOT. The LLOQ was 25 IU/mL, and <LLOQ, TND was 10 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. N=Number of participants analyzed for this outcome. | Follow-up Week 48 |