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

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

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

Study Overview

• Status: Completed
• Conditions: Hepatitis C; Pharmacokinetics
• Intervention / Treatment: Drug: Placebo; Drug: ribavirin (RBV); Drug: pegylated interferon (PegIFN) alfa-2a; Drug: BI 201335 NA low placebo; Drug: BI 201335 NA low; Drug: BI 201335 NA high; Drug: BI 201335 NA high placebo

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Kurashiki, Okayama, Japan
    • 1220.14.003 Boehringer Ingelheim Investigational Site
  • Minato-ku, Tokyo, Japan
    • 1220.14.001 Boehringer Ingelheim Investigational Site
  • Nishinomiya, Hyogo, Japan
    • 1220.14.002 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: July 21, 2009
• First Submitted That Met QC Criteria: July 27, 2009
• First Posted (Estimate): July 28, 2009

Study Record Updates

• Last Update Posted (Estimate): July 7, 2015
• Last Update Submitted That Met QC Criteria: July 3, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Antineoplastic Agents; Interferons; Ribavirin
• Other Study ID Numbers: 1220.14