Safety, Antiviral Activity and PK of MRD of BI 201335 in Chronic Hepatitis C Patients Both Treatment Naive and -Experienced

Study Overview
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Brief Summary
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This study will investigate safety, antiviral activity, and pharmacokinetics of BI 201335 NA in HCV genotype 1 infected patients treated for 14 days monotherapy followed by BI 201335 NA combination therapy with PegIFN/RBV for an additional 14 days for treatment-naïve patients; or for 28 days as BI 201335 NA combination therapy with PegIFN/RBV for treatment-experienced patients. A secondary objective is to investigate antiviral activity, potential drug-drug interactions and safety of combination therapy of BI 201335 NA and PegIFN/RBV up to 28 days for treatment-naïve patients.

Official Title
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Safety, Antiviral Activity, and Pharmacokinetics of Multiple Rising Oral Doses of BI 201335 NA in Treatment-naïve Patients With Chronic Hepatitis C Infection for 14 Days Monotherapy Followed by Combination With Pegylated Interferon and Ribavirin for an Additional 14 Days (Double-blind, Placebo Controlled), and in Treatment-experienced Patients With Chronic Hepatitis C Infection for 28 Days as Combination Therapy With Pegylated Interferon and Ribavirin (Open-label)

Conditions
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Hepatitis C, Chronic

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


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 1a. For treatment-naïve patients: no prior therapy with interferon, peginterferon, or ribavirin for acute or chronic hepatitis C infection 1b. For treatment-experienced patients: confirmed virological failure during or after combination treatment with an approved dose of alfa-2a or alfa-2b peginterferon combined with ribavirin; such patients must have received at least 12 weeks of therapy with a 90 day washout period prior to screening and must have documentation of medical history prior to enrolment in 1220.2 2. Age 18 years or older 3. Signed informed consent form prior to trial participation 4. Male or female with documented hysterectomy or menopausal female with last menstrual period at least 6 months prior to screening 5. Chronic hepatitis C infection of genotype 1, diagnosed by positive HCV serology test (HCV Ab positive) or detectable HCV RNA at least 6 months prior to screening 6. HCV viral load >= 100,000 IU/mL at screening 7. TSH and T4 within normal limits or adequately controlled thyroid function 8. Histological evidence within 36 months prior to study enrolment of any degree of chronic necroinflammatory activity or the presence of fibrosis (Ishak Grade 1-4 or Metavir Grade 1-3) Exclusion criteria: Patients who have been previously treated with at least one dose of any protease inhibitor for acute or chronic hepatitis C infection Evidence of liver disease due to causes other than chronic HCV infection Positive ELISA for HIV-1 or HIV-2 Hepatitis B virus (HBV) infection based on presence of Hbs Ag or HBV DNA Any previous liver biopsy consistent with cirrhosis Decompensated liver diseases as evidenced by ascites, portal hypertension, jaundice or hepatic encephalopathy Haemophilia Hemoglobinopathy (e.g., thalassemia major or sickle cell anemia) Severe pre-existing psychiatric disease Poorly controlled diabetes mellitus Ischaemic heart disease Chronic obstructive airway disease Autoimmune disease; including autoimmune hepatitis History of alcohol abuse within the past 12 months Hyperbilirubinemia (conjugated bilirubin) >1.5x ULN Alkaline phosphatase >1.5x ULN ALT and AST levels >= 5 x ULN Hemoglobin < 12.0 g/dL for women and < 13.0 g/dL for men White blood cell count < 2000 cells/mm3 Absolute Neutrophil Count < 1500 cells/mm3 Platelet count < 100,000 cells/mm3 Prothrombin time INR (Institutional Normalized Ratio) prolonged to > 1.5 x ULN Usage of any investigational drug within 30 days prior to enrolment; or the planned usage of an investigational drug during the course of the current study Known hypersensitivity to study drugs

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20mg<br>patient to receive 20mg solution BI201335 qd +/- PegIFN/RBV fore 28 days | Drug: BI201335<br>* patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days<br>|
| Experimental: 48mg<br>patient to receive 48mg solution BI201335 qd +/- PegIFN/RBV fore 28 days | Drug: BI201335<br>* patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days<br>|
| Experimental: 120mg<br>patient to receive 120mg solution BI201335 qd +/- PegIFN/RBV fore 28 days | Drug: BI201335<br>* patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days<br>|
| Experimental: 240mg<br>patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days | Drug: BI201335<br>* patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days<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 |
| --- | --- | --- |
| Efficacy: VR (Virologic Response) of >=2 log10 Reduction in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) From Baseline at Any Time up to Day 14 (naïve Patients) or Day 28 (Experienced Patients) | Efficacy endpoint: VR (virologic response) of >=2 log10 reduction in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) from baseline at any time up to Day 14 (naïve patients) or Day 28 (experienced patients). | Baseline and up to 4 weeks | 
| Occurrence of Adverse Events (AEs) During BI201335 + Washout Period | Occurrence of Adverse Events (AEs) during BI201335 + washout period. For placebo patients include all AEs through 30 days after trial discontinuation. | from day 1 and up to 4 weeks + 4 days washout | 
| Occurrence of Serious Adverse Events (SAEs) During BI201335 + Washout Period | Occurrence of Serious Adverse Events (SAEs)during BI201335 or BI201335+ washout period. For placebo patients include all SAEs through 30 days after trial discontinuation. | from day 1 and up to 4 weeks + 4 days washout | 
| Occurrence of Laboratory Test Abnormalities and With Respect to Division of AIDS (DAIDS) Classification and Laboratory Test Values Change Over Time | Occurrence of laboratory test abnormalities and with respect to Division of AIDS (DAIDS) classification and laboratory test values change over time. ALT=Alanine transaminase (SGPT), AST=Aspartate transaminase (SGOT). | Baseline and up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Viral Load Reduction From Baseline up to Day 14 for Treatment-naïve Patients and Day 28 Treatment for Treatment-experienced Patients | Maximum viral load reduction from baseline up to Day 14 for treatment-naïve patients and Day 28 treatment for treatment-experienced patients. | Baseline and up to 4 weeks | 
| Change From Baseline in Viral Load on Day 14 for Treatment-naïve Patients and on Day 28 Treatment for Treatment-experienced Patients | Change from baseline in viral load on Day 14 for treatment-naïve patients and on Day 28 treatment for treatment-experienced patients. | Baseline and up to 4 weeks | 
| Rapid Virologic Response (RVR) | Rapid virologic response (RVR): Plasma HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) on Day 28 for all patients. | week 4 | 
| Early Virologic Response (EVR) | Early Virologic Response (EVR): >=2 log10 reduction in plasma HCV RNA level from baseline at week 12 (day 84) | week 12 | 
| Complete EVR1 (cEVR1) | VL (Viral load) below the limit of quantification of the Roche COBAS Taqman HCV/HPS assay (25 IU/mL) at 4 weeks and below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) at 12 weeks | week 4 and week 12 | 
| Complete EVR2 (cEVR2) | VL below the limit of detection at both 4 weeks and 12 weeks | week 4 and week 12 | 
| End of Treatment Response (ETR) | End of Treatment Response (ETR): Plasma HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) at week 48 (Day 336). | week 48 | 
| Sustained Virologic Response (SVR) | Sustained Virologic Response (SVR): Plasma HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) at week 72 (Day 504). | week 72 | 
| Achievement of an HCV RNA Level Below the Limit of Detection Over Time | Achievement of an HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) over time | from day 1 and up to 4 weeks | 
| Achievement of an HCV RNA Level Below the Limit of Quantification Over Time | Achievement of an HCV RNA Level Below the Limit of quantification of the Roche COBAS Taqman HCV/HPS assay (25 IU/mL) Over Time | from day 1 and up to 4 weeks | 
| Achievement of a >= 2 log10 Reduction in Plasma HCV RNA Level From Baseline Over Time | Achievement of a >= 2 log10 reduction in plasma HCV RNA level from baseline over time. | from day 1 and up to 4 weeks | 
| Occurrence of AEs, by Action Taken With Regard to Study Medication | Occurrence of AEs, by action taken with regard to study medication. | from day 1 and up to 4 weeks | 
| Occurrence of Discontinuations Due to AEs During BI201335 or BI201335+PegIFN/RBV Combination Treatment Period | Occurrence of discontinuations due to AEs during BI201335 or BI201335+PegIFN/RBV combination treatment period. | from day 1 and up to 4 weeks | 
| PK (Pharmacokinetic) Parameter After the First Dose: Cmax ( Maximum Measured Concentration of the Analyte in Plasma) | PK (pharmacokinetic) parameter after the first dose: Cmax ( Maximum measured concentration of the analyte in plasma ). . | Times of -0:15, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, and 16:00 h relative to first administration of trial medication (on day 1) | 
| PK Parameter After the First Dose: Tmax (Time From (Last) Dosing to the Maximum Measured Concentration of the Analyte in Plasma) | PK parameter after the first dose: tmax (Time from (last) dosing to the maximum measured concentration of the analyte in plasma). | Times of -0:15, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, and 16:00 h relative to first administration of trial medication (on day 1) | 
| PK Parameter After the First Dose: AUCτ,1 (Area Under the Concentration-time Curve of the Analyte in Plasma Over a Uniform Dosing Interval τ on Day 1) | PK parameter after the first dose: AUCτ,1 (Area under the concentration-time curve of the analyte in plasma over a uniform dosing interval τ on day 1). | Times of -0:15, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, and 16:00 h relative to first administration of trial medication (on day 1) | 
| PK Parameter at Steady State After the Last Dose: Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ) | PK parameter at steady state after the last dose: Cmax,ss (Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ). | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: Tmax,ss (Time From Last Dosing to the Maximum Measured Concentration of the Analyte in Plasma at Steady State ) | PK parameter at steady state after the last dose: tmax,ss (Time from last dosing to the maximum measured concentration of the analyte in plasma at steady state ). | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: Cmin,ss (Minimum Measured Concentration of the Analyte in Plasma) | PK parameter at steady state after the last dose: Cmin,ss (Minimum measured concentration of the analyte in plasma). | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: AUCτ,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ) | PK parameter at steady state after the last dose: AUCτ,ss ((Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ). | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: t1/2,ss (Terminal Half-life of the Analyte in Plasma at Steady State ) | PK parameter at steady state after the last dose: t1/2,ss (Terminal half-life of the analyte in plasma at steady state [h] ) | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: MRTpo,ss (Mean Residence Time of the Analyte in the Body at Steady State After Oral Administration) | PK parameter at steady state after the last dose: MRTpo,ss (Mean residence time of the analyte in the body at steady state after oral administration [h] ) | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: CL/F,ss (Apparent Clearance of the Analyte in Plasma at Steady State Following Multiple Oral Dose Administration ) | PK parameter at steady state after the last dose (if applicable): CL/F,ss (ss Apparent clearance of the analyte in plasma at steady state following multiple oral dose administration [mL/min] ) | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter at Steady State After the Last Dose: Vz/F,ss (Apparent Volume of Distribution During the Terminal Phase z at Steady State Following an Oral Administration ) | PK parameter at steady state after the last dose: Vz/F,ss (Apparent volume of distribution during the terminal phase z at steady state following an oral administration [L] ) | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28) | 
| PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): AUCτ,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ ) | PK parameter for drug-drug interaction (naïve patients with ≥1 log reduction on Day 10): AUCτ,ss ( Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ ). | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to administration of trial medication in the morning of Day 14 (on day 14) | 
| PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): Cmax,ss | PK parameter for drug-drug interaction (naïve patients with ≥1 log reduction on Day 10): Cmax,ss. | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to administration of trial medication in the morning of Day 14 (on day 14) | 
| PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): Cmin, ss | PK parameter for drug-drug interaction (naïve patients with ≥1 log reduction on Day 10): Cmin, ss. | Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to administration of trial medication in the morning of Day 14 (on day 14) | 
| Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAcmax | For TN patients, comparing exposure on Day 14 to the first dose on Day 1; for TE patients, comparing exposure on Day 28 to the first dose on Day 1. | Day 1, Day 14, and Day 28 | 
| Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAauc | For TN patients, comparing exposure on Day 14 to the first dose on Day 1; for TE patients, comparing exposure on Day 28 to the first dose on Day 1. | Day 1, Day 14, and Day 28 |