Efficacy and Safety of BI 201335 (Faldaprevir) in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-naïve Genotype 1 Hepatitis C Infected Patients (STARTverso 2)

Study Overview
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Brief Summary
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The objective of this trial is to evaluate the efficacy and safety of two different treatment regimens with BI 201335, both in combination with PegIFN/RBV) as compared to standard of care (SOC) with PegIFN/RBV alone.

Official Title
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A Phase III, Randomized, Double Blind and Placebo Controlled Study of Once Daily BI 201335 120 mg for 24 Weeks and BI 201335 240 mg for 12 Weeks in Combination With Pegylated Interferon Alpha and Ribavirin in Treatment Naive Patients With Genotype 1 Chronic Hepatitis C Infection.

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: BI201335
* Drug: PegIFN/RBV
* Drug: BI201335
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Chronic hepatitis C infection, diagnosed by positive anti-HCV antibodies and detected HCV RNA at screening in addition to: positive anti-HCV antibodies or detected HCV RNA at least 6 months prior to screening; or, liver biopsy consistent with chronic HCV infection. HCV genotype 1 infection confirmed by genotypic testing at screening. Therapy-naïve to interferon, pegylated interferon, ribavirin or any antiviral / immunomodulatory drug for acute or chronic HCV infection. HCV RNA = 1,000 IU/mL at screening Documentation of a liver biopsy within 3 years or fibroscan within 6 months of the screening visit. Note: If cirrhosis has been previously demonstrated on a biopsy, then biopsies obtained more than 3 years before enrolment need not be repeated. Biopsies can be waived for patients who would be placed at risk from the procedure. Inability to do a liver biopsy should not exclude patients from a trial. Age 18 to 70 years Female patients: (c) with documented hysterectomy, (d) who have had both ovaries removed, (e) with documented tubal ligation, (f) who are post-menopausal with last menstrual period at least 12 months prior to screening, or (g) of childbearing potential with a negative serum pregnancy test at screening and Day 1, that, if sexually active, agree to use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin in addition to the consistent and correct use of a condom. Patients must agree not to breast-feed at any time from the date of screening until 7 months after the last dose of ribavirin. Medically accepted methods of contraception for females in this trial are ethinyl estradiol-containing contraceptives, diaphragm with spermicide substance and intra-uterine device. Male patients: who are documented to be sterile, or who are without pregnant female partner(s) and consistently and correctly use a condom while their female partner(s) (if of child-bearing potential) use one of the appropriate medically accepted methods of birth control from the date of screening until 7 months after the last dose of ribavirin. It is in the responsibility of the male patient to ensure that his partner(s) is not pregnant prior to screening into the study or becomes pregnant during the treatment and the observation phase. Signed informed consent form prior to trial participation Exclusion criteria: HCV infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening. Evidence of acute or chronic liver disease due to causes other than chronic HCV infection. HIV co-infection. Hepatitis B virus (HBV) infection based on presence of HBs-Ag. Active malignancy, or history of malignancy within the last 5 years prior to screening (with an exception of appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the uterine cervix) Active or, history of alcohol or illicit drug abuse other than cannabis within the past 12 months A condition that is defined as one which in the opinion of investigator may put the patient at risk because of participation in this study, may influence the results of this study, or limit the patient¿s ability to participate in this study. Usage of any investigational drugs within 28 days prior to screening, or planned usage of an investigational drug during the course of this study. Received concomitant systemic antiviral, hematopoietic growth factor, or immunomodulatory treatment within 28 days prior to screening. Patients being treated with oral antivirals such as acyclovir, famciclovir or valacyclovir for recurrent herpes simplex infection; or with oseltamivir or zanamivir for influenza A infection, may be screened. Received silymarin (milk thistle), glycyrrhizin, or Sho-saiko-to (SST) within 28 days prior to screening and throughout the treatment phase. Known hypersensitivity to any ingredient of the study drugs. Alpha fetoprotein value >100 ng/mL at screening; if >20 ng/mL and =100 ng/mL, patients may be included if there is no evidence of liver cancer in an appropriate imaging study (e.g., ultrasound, CT scan, or MRI) within last 6 months prior to randomization (Visit 2). Decompensated liver disease, or history of decompensated liver disease, as defined by the presence of: hepatic encephalopathy, ascites, or esophageal variceal bleeding and/or laboratory results of any of the following: International normalized ratio (INR) of =1.7 Serum Albumin =3.5 g/dL Serum total bilirubin =2.0 mg/dL (except when the increase is predominately due to unconjugated bilirubin and related to Gilberts syndrome). Pre-existing psychiatric condition that could interfere with the subject¿s participation in and completion of the study including but not limited to prior suicidal attempt, schizophrenia, major depression syndrome, severe anxiety, severe personality disorder, a period of disability or impairment due to a psychiatric disease within the past 5 years.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PegIFN/RBV<br>48 weeks | Drug: PegIFN/RBV<br> <br> |
| Experimental: BI 201335 for 24 weeks<br>BI 201 335 QD dosing in combination with IFN/RBV | Drug: PegIFN/RBV<br> <br> Drug: BI201335<br>* QD (once daily) BI 201335<br>|
| Experimental: BI201335 for 12 weeks<br>BI 201335 QD doing in combination with PEFG IFN/RBV | Drug: BI201335<br>* QD BI 201335<br>Drug: PegIFN/RBV<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response 12 Weeks Post Treatment (SVR12) | Percentage of participants with sustained virologic response 12 weeks post treatment (SVR12) defined as plasma Hepatitis C virus Ribonucleic acid (HCV RNA) level<25 IU/mL (undetected) 12 weeks after the originally planned treatment duration. | 12 weeks post treatment, up to 60 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response 24 Weeks Post-treatment (SVR24) | Percentage of participants with sustained virologic response 24 weeks post-treatment (SVR24), defined as plasma HCV RNA level < 25 IU/mL (undetected) 24 weeks after the originally planned treatment duration. Hepatitis C virus Ribonucleic acid (HCV RNA) | 24 weeks post treatment, up to 72 weeks | 
| Early Treatment Success (ETS) | Percentage of participants with early treatment success (ETS), defined as a plasma HCV RNA level <25 IU/mL (detected or undetected) at week 4 and HCV RNA <25 IU/mL (undetected) at week 8. | Week 4 and week 8 | 
| ALT Normalisation: ALT in Normal Range at End of Treatment (EOT) When SVR12=YES | The number of participants with alanine aminotransferase (ALT) in normal range at end of treatment (EOT) when patients have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| ALT Normalisation: ALT in Normal Range at End of Treatment (EOT) When SVR12= NO | The number of participants with alanine aminotransferase (ALT) in normal range at end of treatment (EOT) when patients do not have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| ALT Normalisation: ALT in Normal Range 12 Weeks Post-treatment, When SVR12=YES | The number of participants with alanine aminotransferase (ALT) in normal range 12 weeks post-treatment when patients have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| ALT Normalisation: ALT in Normal Range 12 Weeks Post-treatment, When SVR12=NO | The number of participants with alanine aminotransferase (ALT) in normal range 12 weeks post-treatment when patients do not have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| AST Normalisation: AST in Normal Range at End of Treatment (EOT) When SVR12=YES | The number of participants with aspartate aminotransferase (AST) in normal range at the end of treatment when patients have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| AST Normalisation: AST in Normal Range at End of Treatment (EOT) When SVR12=NO | The number of participants with aspartate aminotransferase (AST) in normal range at the end of treatment when patients do not have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| AST Normalisation: AST in Normal Range 12 Weeks Post-treatment, When SVR12=YES | The number of participants with aspartate aminotransferase (AST) in normal range 12 weeks post-treatment when patients have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks | 
| AST Normalisation: AST in Normal Range 12 Weeks Post-treatment, When SVR12=NO | The number of participants with aspartate aminotransferase (AST) in normal range 12 weeks post-treatment when patients do not have sustained virological response 12 weeks post-treatment. BL = Baseline | 12 weeks post treatment, up to 60 weeks |