This Trial Evaluates Safety, Pharmacokinetic Profile and Anti-viral Response of BI 207127 and BI 201335 for Patients With Chronic Hepatitis C

Study Overview
=================
Brief Summary
-----------------
The objective of this trial is to investigate tolerability, safety, pharmacokinetics and antiviral activity of BI 207127 NA in combination with BI 201335 NA and ribavirin for 8 weeks in Japanese treatment-naive patients with chronic GT-1 HCV infection.

Official Title
-----------------
An Open-label, Ascending Dose, Phase II Study to Evaluate Tolerability, Safety, Antiviral Activity, and Pharmacokinetics of BI 207127 NA in Combination With BI 201335 NA and Ribavirin for 8 Weeks in Treatment-naïve Japanese Patients With Genotype 1chronic Hepatitis C Virus Infection

Conditions
-----------------
Hepatitis C, Chronic

Intervention / Treatment
-----------------
* Drug: BI 207127 NA
* Drug: peginterferon
* Drug: Ribavirin
* Drug: Ribavirin
* Drug: BI 207127 NA
* Drug: BI 201335 NA
* Drug: BI 201335 NA
* Drug: peginterferon


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Chronic hepatitis C, diagnosed by positive anti-hepatitis C virus(HCV) antibodies and detected HCV ribonucleic acid(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 infection of genotype 1 confirmed by genotypic testing at screening Therapy-naïve to interferon, pegylated interferon, ribavirin or any antiviral / immunomodulatory drug for acute or chronic HCV infection. Plasma HCV RNA = 100,000 IU/mL at screening Exclusion criteria: Hepatitis C infection of mixed genotype (1/2, 1/3, and 1/4) diagnosed by genotypic testing at screening Human immunodeficiency virus (HIV) co-infection Decompensated liver disease, or history of decompensated liver disease Body weight < 40 or > 125 kg at screening Hemoglobin <12.0g/dL for women and <13.0g/dL for men at screening White blood cell count <3000 cells/mm3 at screening Absolute neutrophil count < 1,500 cells/mm3 at screening Platelet count < 90,000 /mm3 at screening Serum creatinine > 1.5xUpper Limit of Normal range(ULN) or creatinine clearance =50 mL/min at screening

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 207127 NA, BI 201335 NA(high dose), R<br>Patients receive BI 207127 NA,BI 201335 NA(high dose) and RBV for 8 wks followed by BI 201335 NA,PegIFN/RBV for 24 wks | Drug: peginterferon<br>* per package insert<br>Drug: Ribavirin<br>* per weight BID<br>Drug: BI 207127 NA<br>* one fix dose<br>Drug: BI 201335 NA<br>* high dose<br>|
| Experimental: BI 207127 NA,BI 201335 NA(low dose),RBV<br>Patients receive BI 207127 NA,BI 201335 NA(low dose) and RBV for 8 wks followed by BI 201335 NA,PegIFN/RBV for 24 wks | Drug: BI 207127 NA<br>* one fix dose<br>Drug: Ribavirin<br>* per weight BID<br>Drug: BI 201335 NA<br>* low dose<br>Drug: peginterferon<br>* per package insert<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Drug-related Adverse Events | Number of patients with investigator defined drug-related Adverse Events | From first dose of study medication until 30 days after last dose of study medication, up to 199 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Virological Response at Week 4 | Percentage of participants with plasma HCV RNA (hepatitis C virus (HCV) ribonucleic acid (RNA)) level <25 IU/mL (undetected or detected) at week 4. | 4 weeks | 
| Percentage of Participants With Virological Response at Week 8 | Percentage of participants with plasma HCV RNA (hepatitis C virus ribonucleic acid ) level <25 IU/mL (undetected or detected) at week 8. | 8 weeks | 
| Maximum Measured Concentration (Cmax) of Deleobuvir | Maximum measured concentration of BI 207127 (Deleobuvir) in plasma following the morning dose of Nth day (Cmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Time From Last Dosing to the Maximum Concentration (Tmax) of Deleobuvir | Time from last dosing to the maximum concentration of Deleobuvir (BI 207127) in plasma after the morning dose of Nth day (Tmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Area Under the Curve (AUC) of Deleobuvir | Area under the concentration time curve (AUC) of the analyte in plasma after the morning dose on the Nth day (AUCτ,N) and at steady state (AUCτ,ss), over a uniform dosing interval τ. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Maximum Measured Concentration (Cmax) of Faldaprevir | Maximum measured concentration of Faldaprevir (BI 201335 ZW) in plasma following the morning dose of Nth day (Cmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Time From Last Dosing to the Maximum Concentration (Tmax) of Faldaprevir | Time from last dosing to the maximum concentration of Faldaprevir (BI 201335 ZW) in plasma after the morning dose of Nth day (Tmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Area Under the Curve (AUC) of Faldaprevir | Area under the concentration time curve (AUC) of the analyte in plasma after the morning dose on the Nth day (AUCτ,N) and at steady state (AUCτ,ss), over a uniform dosing interval τ. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Maximum Measured Concentration (Cmax) of BI 208333 | Maximum measured concentration of BI 208333 (a metabolite of Deleobuvir) in plasma following the morning dose of Nth day (Cmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Time From Last Dosing to the Maximum Concentration (Tmax) of BI 208333 | Time from last dosing to the maximum concentration of BI 208333 (a metabolite of Deleobuvir) in plasma after the morning dose of Nth day (Tmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Area Under the Curve (AUC) of BI 208333 | Area under the concentration time curve (AUC) of the analyte in plasma after the morning dose on the Nth day (AUCτ,N) and at steady state (AUCτ,ss), over a uniform dosing interval τ. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Maximum Measured Concentration (Cmax) of CD 6168 | Maximum measured concentration of CD 6168 (a metabolite of Deleobuvir) in plasma following the morning dose of Nth day (Cmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 1, 11 and 57 | 
| Time From Last Dosing to the Maximum Concentration (Tmax) of CD 6168 | Time from last dosing to the maximum concentration of CD 6168 (a metabolite of Deleobuvir) in plasma after the morning dose of Nth day (Tmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Area Under the Curve (AUC) of CD 6168 | Area under the concentration time curve (AUC) of the analyte in plasma after the morning dose on the Nth day (AUCτ,N) and at steady state (AUCτ,ss), over a uniform dosing interval τ. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Maximum Measured Concentration (Cmax) of CD 6168-AG | Maximum measured concentration of CD 6168-AG (a metabolite of Deleobuvir) in plasma following the morning dose of Nth day (Cmax,N). AG=acylglucuronide. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 1, 11 and 57 | 
| Time From Last Dosing to the Maximum Concentration (Tmax) of CD 6168-AG | Time from last dosing to the maximum concentration of CD 6168-AG (a metabolite of Deleobuvir) in plasma after the morning dose of Nth day (Tmax,N). AG=acylglucuronide. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Area Under the Curve (AUC) of CD 6168-AG | Area under the concentration time curve (AUC) of the analyte in plasma after the morning dose on the Nth day (AUCτ,N) and at steady state (AUCτ,ss), over a uniform dosing interval τ. AG=acylglucuronide. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Maximum Measured Concentration (Cmax) of RBV | Maximum measured concentration of ribavirin (RBV) in plasma following the morning dose of Nth day (Cmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on days 1 and 57 | 
| Time From Last Dosing to the Maximum Concentration (Tmax) of RBV | Time from last dosing to the maximum concentration of ribavirin (RBV) in plasma after the morning dose of Nth day (Tmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on days 1 and 57 | 
| Area Under the Curve (AUC) of RBV | Area under the concentration time curve (AUC) of ribavirin (RBV) in plasma after the morning dose on the Nth day (AUCτ,N) and at steady state (AUCτ,ss), over a uniform dosing interval τ. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on days 1 and 57 | 
| Cmax Accumulation Ratio (RA,Cmax,N) of Deleobuvir | Accumulation ratio of BI 207127 (Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of Cmax after the morning dose of the Nth day and after the first dose (RA,Cmax,N), and ratio of the Cmax,ss of Deleobuvir versus itself (RA,Cmax,Met,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| AUC Accumulation Ratio of Deleobuvir | Accumulation ratio of BI 207127 (Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of AUC after the morning dose of the Nth day and after the first dose (RA,AUC,N), and ratio of the AUC,ss of Deleobuvir versus itself (RA,AUC,Met,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Mean Residence Time (MRTpo,ss) of Deleobuvir | Mean residence time of BI 207127 (Deleobuvir) in the body after oral administration at steady state (MRTpo,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on day 57 | 
| Apparent Clearance (CL/F,ss) of Deleobuvir | Apparent clearance of BI 207127 (Deleobuvir) in plasma following extravascular administration on the 57th day (CL/F,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on day 57 | 
| Predose Measured Concentration of Deleobuvir | Predose measured concentration of BI 207127 (Deleobuvir) in plasma before the morning dose of the Nth day (Cpre,N) and at steady state (Cpre,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 11 and 57 | 
| Cmax Accumulation Ratio (RA,Cmax,N) of Faldaprevir | Accumulation ratio of Faldaprevir (BI 201335 ZW) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of Cmax after the morning dose of the Nth day and after the first dose (RA,Cmax,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| AUC Accumulation Ratio of Faldaprevir | Accumulation ratio of Faldaprevir (BI 201335 ZW) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of AUC after the morning dose of the Nth day and after the first dose (RA,AUC,N). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Mean Residence Time (MRTpo,ss) of Faldaprevir | Mean residence time of Faldaprevir (BI 201335 ZW) in the body after oral administration at steady state (MRTpo,ss). This endpoint was not analysed as the parameter was not calculable for all patients in both treatment groups. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on day 57 | 
| Apparent Clearance (CL/F,ss) of Faldaprevir | Apparent clearance of Faldaprevir (BI 201335 ZW) in plasma following extravascular administration on the 57th day (CL/F,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on day 57 | 
| Predose Measured Concentration of Faldaprevir | Predose measured concentration of Faldaprevir (BI 201335 ZW) in plasma before the morning dose of the Nth day (Cpre,N) and at steady state (Cpre,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 11 and 57 | 
| Cmax Accumulation Ratio of BI 208333 | Accumulation ratio of BI 208333 (a metabolite of Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of Cmax after the morning dose of the Nth day and after the first dose (RA,Cmax,N), and ratio of the Cmax,ss of BI 208333 versus Cmax,ss of Deleobuvir (RA,Cmax,Met,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| AUC Accumulation Ratio of BI 208333 | Accumulation ratio of BI 208333 (a metabolite of Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of AUC after the morning dose of the Nth day and after the first dose (RA,AUC,N), and ratio of the AUC,ss of BI 208333 versus AUC,ss of Deleobuvir (RA,AUC,Met,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 1, 11 and 57 | 
| Mean Residence Time (MRTpo,ss) of BI 208333 | Mean residence time of BI 208333 (a metabolite of Deleobuvir) in the body after oral administration at steady state (MRTpo,ss). This endpoint was not analysed as the parameter was not calculable for all patients in both treatment groups. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on day 57 | 
| Predose Measured Concentration of BI 208333 | Predose measured concentration of BI 208333 (a metabolite of Deleobuvir) in plasma before the morning dose of the Nth day (Cpre,N) and at steady state (Cpre,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and 23h 50min after drug administration on days 11 and 57 | 
| Cmax Accumulation Ratio of CD 6168 | Accumulation ratio of CD 6168 (a metabolite of Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of Cmax after the morning dose of the Nth day and after the first dose (RA,Cmax,N), and ratio of the Cmax,ss of CD 6168 versus Cmax,ss of Deleobuvir (RA,Cmax,Met,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 1, 11 and 57 | 
| AUC Accumulation Ratio of CD 6168 | Accumulation ratio of CD 6168 (a metabolite of Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of AUC after the morning dose of the Nth day and after the first dose (RA,AUC,N), and ratio of the AUC,ss of CD 6168 versus AUC,ss of Deleobuvir (RA,AUC,Met,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 1, 11 and 57 | 
| Mean Residence Time (MRTpo,ss) of CD 6168 | Mean residence time of CD 6168 (a metabolite of Deleobuvir) in the body after oral administration at steady state (MRTpo,ss). This endpoint was not analysed as the parameter was not calculable for all patients in both treatment groups. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on day 57 | 
| Predose Measured Concentration of CD 6168 | Predose measured concentration of CD 6168 (a metabolite of Deleobuvir) in plasma before the morning dose of the Nth day (Cpre,N) and at steady state (Cpre,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 11 and 57 | 
| Cmax Accumulation Ratio of CD 6168-AG | Accumulation ratio of CD 6168-AG (a metabolite of Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of Cmax after the morning dose of the Nth day and after the first dose (RA,Cmax,N), and ratio of the Cmax,ss of CD 6168-AG versus Cmax,ss of Deleobuvir (RA,Cmax,Met,ss). AG=acylglucuronide. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 1, 11 and 57 | 
| AUC Accumulation Ratio of CD 6168-AG | Accumulation ratio of CD 6168-AG (a metabolite of Deleobuvir) in plasma after the administration of the Nth day over a uniform dosing interval tau, expressed as a ratio of AUC after the morning dose of the Nth day and after the first dose (RA,AUC,N), and ratio of the AUC,ss of CD 6168-AG versus AUC,ss of Deleobuvir (RA,AUC,Met,ss). AG=acylglucuronide. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 1, 11 and 57 | 
| Mean Residence Time (MRTpo,ss) of CD 6168-AG | Mean residence time of CD 6168-AG (a metabolite of Deleobuvir) in the body after oral administration at steady state (MRTpo,ss). AG=acylglucuronide. This endpoint was not analysed as the parameter was not calculable for all patients in both treatment groups. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on day 57 | 
| Predose Measured Concentration of CD 6168-AG | Predose measured concentration of CD 6168-AG (a metabolite of Deleobuvir) in plasma before the morning dose of the Nth day (Cpre,N) and at steady state (Cpre,ss). AG=acylglucuronide. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h, 11h 50min and and 23h 50min after drug administration on days 11 and 57 | 
| AUC Accumulation Ratio of RBV | Accumulation ratio of ribavirin (RBV) in plasma after the administration of the 57th day over a uniform dosing interval tau, expressed as a ratio of AUC after the morning dose of the 57th day and after the first dose (RA,AUC,57). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on days 1 and 57 | 
| Cmax Accumulation Ratio (RA,Cmax,57) of RBV | Accumulation ratio of ribavirin (RBV) in plasma after the administration of the 57th day over a uniform dosing interval tau, expressed as a ratio of Cmax after the morning dose of the 57th day and after the first dose (RA,Cmax,57). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on days 1 and 57 | 
| Mean Residence Time (MRTpo,ss) of RBV | Mean residence time of ribavirin (RBV) in the body after oral administration at steady state (MRTpo,ss). This endpoint was not analysed as the parameter was not calculable for all patients in both treatment groups. | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on day 57 | 
| Predose Measured Concentration of RBV | Predose measured concentration of ribavirin (RBV) in plasma before the morning dose of the Nth day (Cpre,N) and at steady state (Cpre,ss). | 10 minutes (min) before drug administration and 2 hours (h), 4h, 6h, 8h, 10h and 11h 50min after drug administration on days 11 and 57 |