Study of Daclatasvir (BMS-790052) and Simeprevir (TMC435) in Patients With Genotype 1 Chronic Hepatitis C Virus

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of daclatasvir and simeprevir with and without ribavirin for genotype 1 chronic hepatitis C virus infection in patients who are treatment-naive or null responders to previous pegylated interferon/ribavirin therapy.

Official Title
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A Phase 2, Open-Label Study of Daclatasvir (BMS-790052) and TMC435 in Combination With or Without Ribavirin (RBV) For Treatment-Naive Subjects or Null Responders to Prior Peginterferon Alfa (PegIFN)/RBV Therapy With Genotype 1 Chronic Hepatitis C

Conditions
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Hepatitis C Virus

Intervention / Treatment
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* Drug: Daclatasvir
* Drug: Simeprevir
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Hepatitis C virus (HCV) genotype 1a or 1b Males and females, ≥18 years of age HCV RNA ≥10,000 IU/mL Participants with compensated cirrhosis are permitted Advanced fibrosis (F3/F4) is capped at approximately 35% of the total treated population with a minimum of 20% F4 patients If no cirrhosis, a liver biopsy within 3 years prior to enrollment If cirrhosis is present, any prior liver biopsy Key Exclusion Criteria: Liver or any other transplant (other than cornea and hair) Evidence of a medical condition contributing to chronic liver disease other than HCV infection 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 Evidence of decompensated liver disease including, but not limited to, radiologic criteria, a history or presence of ascites, bleeding varices, or hepatic encephalopathy Patients infected with HIV or hepatitis B virus Gastrointestinal disease impacting absorption of study drug Uncontrolled diabetes or hypertension Prior exposure to an HCV direct-acting agent Any criteria that would exclude the patient from receiving ribavirin Absolute neutrophil count <1.5*1,000,000,000 cells/L (<1.2*1,000,000,000 cells/L for Black/African Americans) Platelets <90*1,000,000,000 cells/L Hemoglobin <12 g/dL for females, <13 g/dL for males Alanine aminotransferase ≥5*upper limit of normal In patients without cirrhosis, total bilirubin ≥2 mg/dL unless patient has a documented history of Gilbert's disease In patients with cirrhosis, total bilirubin o ≥1.5 mg/dL International normalized ratio ≥1.7 QTcF or QTcB >500 mSec Creatinine clearance ≤50 mL/min Alpha fetoprotein (AFP) >100 ng/mL OR AFP ≥50 ng/mL and ≤100 ng/mL requiring liver ultrasound Albumin <3.5 g/dL

Ages Eligible for Study
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Minimum Age: 18 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: Cohort 1: (Genotype 1b) Daclatasvir + Simeprevir<br>Participants with hepatitis C virus genotype 1b received daclatasvir, 30 mg, once daily with or without food + simeprevir, 150 mg, once daily with a meal for 12 weeks | Drug: Daclatasvir<br>* Tablets, oral, 30 mg, once daily<br>* Other names: BMS-790052;Drug: Simeprevir<br>* Capsule, oral, 150 mg, once daily<br>* Other names: TMC435;|
| Experimental: Cohort 2: (Genotype 1b) Daclatasvir + Simeprevir + Ribavirin<br>Participants with hepatitis C virus genotype 1b received daclatasvir, 30 mg, once daily with or without food + simeprivir, 150 mg, once daily with a meal + ribavirin, twice daily with food (patients weighing <75 kg received a total ribavirin dose of 1000 mg per day; those weighing >=75 kg received 1200 mg per day) for 12 weeks. | Drug: Daclatasvir<br>* Tablets, oral, 30 mg, once daily<br>* Other names: BMS-790052;Drug: Simeprevir<br>* Capsule, oral, 150 mg, once daily<br>* Other names: TMC435;|
| Experimental: Cohort 3: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin<br>Participants with hepatitis C virus genotype 1a received daclatasvir, 30 mg, once daily with or without food + simeprevir, 150 mg, once daily with a meal + ribavirin, twice daily with food (patients weighing <75 kg received a total ribavirin dose of 1000 mg per day; those weighing >=75 kg received 1200 mg per day) for 12 weeks. | Drug: Daclatasvir<br>* Tablets, oral, 30 mg, once daily<br>* Other names: BMS-790052;Drug: Simeprevir<br>* Capsule, oral, 150 mg, once daily<br>* Other names: TMC435;Drug: Ribavirin<br>* Tablets, oral, 500-600 mg, twice daily<br>|
| Experimental: Cohort 4: (Genotype 1a) Daclatasvir + Simeprevir + Ribavirin<br>Participants with hepatitis C virus genotype 1a received daclatasvir, 30 mg, once daily with or without food + simeprivir, 150 mg, once daily with a meal + ribavirin, twice daily with food (patients weighing <75 kg received a total ribavirin dose of 1000 mg per day; those weighing >=75 kg received 1200 mg per day. | Drug: Daclatasvir<br>* Tablets, oral, 30 mg, once daily<br>* Other names: BMS-790052;Drug: Simeprevir<br>* Capsule, oral, 150 mg, once daily<br>* Other names: TMC435;Drug: Ribavirin<br>* Tablets, oral, 500-600 mg, twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12) | SVR12 rate was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | Post Treatment Week 12 (Follow-up period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Rapid Virologic Response (RVR) at Week 4 | RVR was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at Week 4. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | Week 4 | 
| Percentage of Participants With Complete Early Virologic Response (cEVR) | cEVR was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | Week 12 | 
| Percentage of Participants With Extended Rapid Virologic Response (eRVR) | eRVR were defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at both Week 4 and Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | Week 4 and Week 12 | 
| Percentage of Participants With End of Treatment Response (EOTR) | EOTR were defined as hepatitis C virus (HCV) RNA levels <lower limit of quantitation, target not detected at end of treatment. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | End of treatment (Week 24) | 
| Percentage of Participants With Sustained Virologic Response at Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories | Participants were categorized into 3 genotypes based on single nucleotide polymorphisms in the IL28B gene. SVR12 was defined as hepatitis C virus (HCV) RNA levels below lower limit of quantitation, target detected or target not detected at follow-up Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. | Baseline, post-treatment Week 12 (Follow-up period) | 
| Number of Participants With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died | AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. 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. Based on the severity, AEs were categorized as Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. | From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24) |