Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Oral Doses of BI 201335 as Softgel Capsule in Naive Hepatitis C Virus (HCV) Patients

Study Overview
=================
Brief Summary
-----------------
The current Standard of Care (SOC) for chronic HCV infection, which is pegylated interferon-alfa as combination therapy with ribavirin for 24-48 weeks of treatment, is effective in only part of the patients and is often associated with severe adverse effects leading to discontinuation of treatment and dose modifications. A number of compounds with direct activity are currently under clinical development, incl. BI 201335. BI 201335 works by preventing the Hepatitis C virus from replicating by binding to the HCV protease (enzyme). The main purpose of this clinical trial with BI 201335 is to see how well BI 201335 works and how safe BI 201335 is to use daily in combination with PegIFN and RBV in HCV infected patients

Official Title
-----------------
Safety, Pharmacokinetics and Antiviral Effect of BI 201335 NA in HCV-1 Infected Patients Treated for 28 Days for Treatment naïve and Experienced Patients Treated in Combination With Peg Interferon Alfa-2a and Ribavirin

Conditions
-----------------
Hepatitis C, Pharmacokinetics

Intervention / Treatment
-----------------
* Drug: ribavirin (RBV)
* Drug: pegylated interferon (PegIFN) alfa-2a
* Drug: pegylated interferon (PegIFN) alfa-2a
* Drug: ribavirin (RBV)
* Drug: BI 201335 NA low placebo
* Drug: pegylated interferon (PegIFN) alfa-2a
* Drug: ribavirin (RBV)
* Drug: BI 201335 NA high
* Drug: BI 201335 NA low
* Drug: BI 201335 NA high placebo
* Drug: BI 201335 NA high
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: chronic HCV genotype-1; high viral load Exclusion criteria: Mixed genotype (1/2, 1/3, or 1/4), diagnosed by genotypic testing at screening Previous treatment with protease inhibitor

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 201335 NA low TN<br>patient to receive a capsule containing low dose of BI 201335 NA/Drug for treatment-naive (TN) patients | Drug: pegylated interferon (PegIFN) alfa-2a<br>* pegylated interferon (PegIFN) alfa-2a<br>Drug: BI 201335 NA low placebo<br>* Placebo<br>Drug: ribavirin (RBV)<br>* ribavirin (RBV)<br>Drug: BI 201335 NA low<br>* BI 201335 NA<br>|
| Experimental: BI 201335 NA high TN<br>patient to receive a capsule containing high dose of BI 201335 NA/Drug for treatment-naive (TN )patients | Drug: ribavirin (RBV)<br>* ribavirin (RBV)<br>Drug: pegylated interferon (PegIFN) alfa-2a<br>* pegylated interferon (PegIFN) alfa-2a<br>Drug: BI 201335 NA high<br>* BI 201335 NA high<br>Drug: BI 201335 NA high placebo<br>* placebo<br>|
| Experimental: BI 201335 NA high TE<br>patient to receive a capsule containing high dose of BI 201335 NA/Drug for treatment-experienced (TE) patients | Drug: pegylated interferon (PegIFN) alfa-2a<br>* pegylated interferon (PegIFN) alfa-2a<br>Drug: ribavirin (RBV)<br>* ribavirin (RBV)<br>Drug: BI 201335 NA high<br>* BI 201335 NA high<br>|
| Placebo Comparator: Placebo in Treatment Naive (TN) Patients<br> | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Investigator Defined Drug-related Adverse Events in Triple Combination Therapy | Drug-related AEs were defined as those whose causal relationship with any one of the investigational products was considered by the investigator. | 4 weeks | 
| Number of Patients With Possible Clinically Significant Laboratory Abnormalities in Triple Combination Therapy | Frequency of patients with possible clinically significant abnormalities or clinically significant laboratory test value changes over time in triple combination therapy for treatment naive patients and treatment experienced patients. | 4 weeks | 
| Assessment of Tolerability in Triple Combination Therapy | An assessment of tolerability for the safety of the triple combination therapy with BI 201335 NA, PegIFN α -2a and RBV. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Week 2 Virological Response (W2VR) | Number of patients satisfying W2VR (plasma HCV RNA (Hepatitis C Virus Ribonucleic acid) level below the limit of quantification (BLQ)) | 2 weeks | 
| Week 4 Virological Response (W4VR) | Number of patients satisfying W4VR (plasma HCV RNA level below the limit of quantification (BLQ)) | 4 weeks | 
| Rapid Virological Response (RVR) | Number of patients satisfying RVR (plasma HCV RNA level below the limit of detection (BLD) at Week 4) | 4 weeks | 
| Change From Baseline in HCV Viral Load | Change form baseline in HCV viral load (log10) after 4 weeks | baseline and week 4 | 
| Day 28 Virologic Response | Number of patients with HCV viral load reduction >= 2 log10 at Week 4 | 4 weeks | 
| Early Virological Response (EVR) | Number of patients with reduction >= 2 log10 in plasma HCV RNA level at Week 12 | 12 Weeks | 
| Complete Early Virological Response (cEVR) | Number of patients with plasma HCV RNA level BLD at Week 12 | 12 weeks | 
| End of Treatment Response (ETR) | Number of patients with plasma HCV RNA level BLD at week 48 | 48 weeks | 
| Sustained Virologic Response (SVR) | Number of patients with plasma HCV RNA level BLD 24 weeks after treatment completion | 72 weeks | 
| Number of Participants With Investigator Defined Drug-related Adverse Events in Standard of Care (SOC) With PegIFN α-2a and RBV | Drug-related AEs in SOC treatment period were defined as those whose causal relationship with any one of the investigational products was considered by the investigator. | 44 weeks | 
| Number of Patients With Possible Clinically Significant Laboratory Abnormalities in Standard of Care (SOC) With PegIFN α-2a and RBV | Frequency of patients with possible clinically significant abnormalities or clinically significant laboratory test value changes over time in SOC period for treatment naive patients and treatment experienced patients. | 44 weeks | 
| Assessment of Tolerability in Standard of Care (SOC) With PegIFN α -2a and RBV | An assessment of tolerability for the safety of the SOC with PegIFN alfa-2a and RBV. | 44 weeks | 
| AUCτ,1 for BI 201335 ZW | Area under the curve (AUC) concentration after the first dose of BI 201335 ZW | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose | 
| Cmax of BI 201335 ZW | Maximum concentration of BI 201335 ZW after multiple oral admin. of BI 201335 NA with RBV and PegIFN alfa-2a | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose | 
| AUCτ,ss of BI 201335 ZW | AUC at steady state after 4 weeks combination of the last dose | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| Cmax,ss of BI 201335 ZW | Maximum concentration of BI 201335 ZW at steady state | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| AUCτ,1 for Ribavirin (RBV) | Area under the plasma concentration curve of RBV after the first dose of placebo or BI 201335 NA with with RBV and PegIFN alfa-2a | -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the first dose | 
| Cmax of RBV | Maximum Plasma concentration of RBV after multiple oral admin. of placebo with RBV and PegIFN alfa-2a | -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the first dose | 
| AUCτ,ss of RBV | Area under the plasma concentration curve of RBV after the multiple oral administration of BI 201335 NA (or placebo) with RBV and PegIFN alfa-2a at steady state | -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the last dose | 
| Cmax,ss of RBV | Maximum Plasma concentration of RBV after multiple oral admin. of BI 201335 NA (or placebo) with RBV and PegIFN alfa-2a at steady state | -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the last dose | 
| Tmax for BI 201335 ZW | Time to maximum plasma concentration (tmax) of BI 201335 ZW after the first dose of BI 201335 NA with RBV and PegIFN alfa-2a | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose | 
| Tmax for RBV | Time to maximum plasma concentration (tmax) of RBV after the first dose of BI 201335 NA with RBV and PegIFN alfa-2a | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose | 
| Tmax, ss for BI 201335 ZW | Time from last dosing to the maximum plasma concentration (tmax) of BI 201335 ZW after the last dose of BI 201335 NA with RBV and PegIFN alfa-2a at steady state | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| Tmax, ss for RBV | Time to the maximum plasma concentration (tmax) of RBV after the last dose of BI 201335 NA with RBV and PegIFN alfa-2a at steady state | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| t1/2,ss for BI 201335 ZW | terminal half-life of the analyte in plasma at steady state (t1/2,ss) | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| Cmin,ss for BI 201335 ZW | Minimum concentration of the analyte (BI 201335 ZW) in plasma over the dosing interval at steady state | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| Cmin,ss for RBV | Minimum concentration of the analyte (RBV) in plasma over the dosing interval at steady state | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| Cavg for BI 201335 ZW | average plasma concentration (Cavg) of BI 201335 ZW | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| Cavg for RBV | average plasma concentration (Cavg) of RBV | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose | 
| CL/F,ss for BI 201335 ZW | apparent clearance of the analyte (BI 201335 ZW) in plasma at steady state (CL/F,ss) following multiple oral administration | 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose |