A Rollover Study of BI 201335 in Combination With Pegylated Interferon-alpha and Ribavirin in Treatment-experienced Genotype 1 Hepatitis C Infected Patients

Study Overview
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Brief Summary
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The objective of this trial is to collect evidence for the safety and efficacy of 24 weeks of treatment with BI 201335 240 mg in combination with 24 or 48 weeks of Pegylated Interferon (PegIFN) and ribavirin (RBV) in treatment experienced patients who have been withdrawn from PegIFN and RBV treatment due to lack of efficacy in the 1220.7, 1220.30 and 1220.47 trials.

Official Title
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A Phase III, Open-label Study of Once Daily BI 201335 240 mg for 24 Weeks in Combination With Pegylated interferon-a (PegIFN) and Ribavirin (RBV) in Patients With Genotype 1 Chronic Hepatitis C Infection Who Failed a Prior PegIFN / RBV Treatment

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: BI 201335
* Drug: PegIFN/RBV


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Chronic hepatitis C infection of GT-1 in patients who failed prior treatment with PegIFN and RBV in the 1220.7, 1220.30 and 1220.47 trials of the BI 201335 Phase III program. Patients from trials 1220.7, 1220.30 and 1220.47 of BI 201335 who have failed treatment with PegIFN/RBV in the placebo groups due to protocol-defined criteria of treatment failure (i.e. either non-response on treatment or relapse after end of treatment [EOT]). Patients must have received at least 4 weeks of assigned trial medication and been compliant with all study procedures. Female patients: with documented hysterectomy, who have had both ovaries removed, with documented tubal ligation, who are post-menopausal with last menstrual period at least 12 months prior to screening, or 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 RBV 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 RBV. Medically accepted methods of contraception for females in this trial are ethinyl estradiol-containing contraceptives, diaphragm with spermicide substance, intra-uterine device and cervical cap. or 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) 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. 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. Female partners of childbearing potential must perform monthly pregnancy tests from the date of screening until 7 months after the last dose of ribavirin (tests will be provided by the sponsor). Signed informed consent form prior to trial participation. Exclusion criteria: Evidence of acute or chronic liver disease due to causes other than chronic HCV infection. Incidental steatosis diagnosed by biopsy is not an exclusion criteria. 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 patients ability to participate in this study Usage of any investigational drugs within 30 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 30 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 enrolment and throughout the treatment phase of this trial. 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). Other exclusion criteria related to pegylated interferon and/or ribavirin restrictions are not listed here.

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 201335 for 24 weeks<br>BI 201335 once daily dose for 24 weeks in combination with PegIFN/RBV for 24 or 48 weeks | Drug: BI 201335<br>* BI 201335 for 24 weeks<br>Drug: PegIFN/RBV<br>* PegIFN/RBV for 48 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virological Response (SVR): Plasma HCV RNA Level < 25 IU/mL | The primary endpoint was SVR12, defined as a plasma Hepatitis C virus (HCV) Ribonucleic acid (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 Virological Response After 24 Weeks of Treatment Discontinuation (SVR24) | Sustained virologic response 24 weeks, defined as a plasma HCV RNA level < 25 IU/mL (undetected) 24 weeks after the originally planned treatment duration. | 24 weeks post treatment, up to 72 weeks | 
| Early Treatment Success (ETS) | 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 | 
| Alanine Aminotransferase (ALT) Normalisation: ALT in Normal Range at End of Treatment (EoT) | This will be presented as the number of patients in/not in normal range from baseline EoT. SVR12 is sustained virological response 12 weeks post-treatment. | Week 24 for relapsers with ETS; Week 48 for relapsers without ETS, and non-relapsers | 
| Alanine Aminotransferase (ALT) Normalisation: ALT in Normal Range at 12 Weeks Post-treatment. | This will be presented as the number of patients in/not in normal range from baseline to 12 weeks post treatment. SVR12 is sustained virological response 12 weeks post-treatment. | 48 weeks for relapsers with ETS; 60 weeks for non-relapsers and relapsers without ETS | 
| Aspartate Aminotransferase (AST) Normalisation: AST in Normal Range at End of Treatment (EoT) | This will be presented as the number of patients in/not in normal range from baseline to EoT. SVR12 is sustained virological response 12 weeks post-treatment. | Week 24 for relapsers with ETS; Week 48 for relapsers without ETS, and non-relapsers. | 
| Aspartate Aminotransferase (AST) Normalisation: AST in Normal Range at 12 Weeks Post-treatment. | This will be presented as the number of patients in/not in normal range from baseline to 12 weeks post treatment. SVR12 is sustained virological response 12 weeks post-treatment. | Week 48 for relapsers with ETS; Week 48 for relapsers without ETS, and non-relapsers | 
| Occurrence of Adverse Events (Overall and by DAIDS Grade) | This outcome measure will be presented as the percentage of subjects with any adverse event (AE). Percentages are calculated using total number of subjects per treatment cohort as the denominator. The intensity of all AEs was evaluated according to the DAIDS (Division of Acquired Immunodeficiency Syndrome) grading scale with AEs of mild, moderate, or severe intensity receiving Grades 1, 2, or 3, respectively. Adverse events judged potentially life threatening received a Grade 4 assessment. | from first intake of study medication until 30 days after discontinuing faldaprevir, up to a maximum of 213 days | 
| Occurrence of Adverse Events Leading to Treatment Discontinuation | This outcome measure will be presented as the percentage of subjects with adverse events leading to discontinuation of Faldaprevir and all study medication. Percentages are calculated using total number of subjects per treatment cohort as the denominator. | from first intake of study medication until 30 days after discontinuing faldaprevir, up to a maximum of 213 days | 
| Occurrence of Serious Adverse Events (SAEs) | This outcome measure will be presented as the percentage of subjects with any serious adverse event (SAE). Percentages are calculated using total number of subjects per treatment cohort as the denominator. | from first intake of study medication until 30 days after discontinuing faldaprevir, up to a maximum of 213 days | 
| Occurrence of Drug-related AEs as Assessed by the Investigator | This outcome measure will be presented as the percentage of subjects with any drug-related AEs as assessed by the investigator. Percentages are calculated using total number of subjects per treatment cohort as the denominator. | from first intake of study medication until 30 days after discontinuing faldaprevir, up to a maximum of 213 days | 
| Laboratory Test Abnormalities by DAIDS Grades | This Outcome measure will be presented as summary of the percentage of patients with worst on-treatment Division of Acquired Immunodeficiency Syndrome (DAIDS) grade laboratory abnormalities for selected analytes (Haemoglobin, Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST) and Bilirubin total) with particular relevance to patients with HCV. | baseline (day 1, after first dose of randomised treatment) up to 7 days after the last intake of study | 
| Changes From Baseline in Laboratory Test Values Over Time [Haemoglobin] | This outcome measure will be presented as the mean value and the standard deviation at baseline, week 4, week 12, the minimum (min) value on treatment, maximum (max) value on treatment and last measured value on treatment. Analytes with particular relevance for patients with HCF have been selected: Haemoglobin, Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST) and Bilirubin total. In this outcome measure Haemoglobin is presented. | baseline (the last observed measurement prior to administration of any randomised study medication), week 4, week 12 (after start of treatment) | 
| Changes From Baseline in Laboratory Test Values Over Time [ALT] | This outcome measure will be presented as the mean value and the standard deviation at baseline, week 4, week 12, the minimum (min) value on treatment, maximum (max) value on treatment and last measured value on treatment. Analytes with particular relevance for patients with HCF have been selected: Haemoglobin, Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST) and Bilirubin total. In this outcome measure ALT is presented. | baseline (the last observed measurement prior to administration of any randomised study medication), week 4, week 12 (after start of treatment) | 
| Changes From Baseline in Laboratory Test Values Over Time [AST] | This outcome measure will be presented as the mean value and the standard deviation at baseline, week 4, week 12, the minimum (min) value on treatment, maximum (max) value on treatment and last measured value on treatment. Analytes with particular relevance for patients with HCF have been selected: Haemoglobin, Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST) and Bilirubin total. In this outcome measure AST is presented. | baseline (the last observed measurement prior to administration of any randomised study medication), week 4, week 12 (after start of treatment) | 
| Changes From Baseline in Laboratory Test Values Over Time [Bilirubin Total] | This outcome measure will be presented as the mean value and the standard deviation at baseline, week 4, week 12, the minimum (min) value on treatment, maximum (max) value on treatment and last measured value on treatment. Analytes with particular relevance for patients with HCF have been selected: Haemoglobin, Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST) and Bilirubin total. In this outcome measure Bilirubin total is presented. | baseline (the last observed measurement prior to administration of any randomised study medication), week 4, week 12 (after start of treatment) |