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

• ClinicalTrials.gov Identifier: NCT00947349
• Recruitment Status: Completed
• First Posted: July 28, 2009
• Results First Posted: July 7, 2015
• Last Update Posted: July 7, 2015
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

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

Condition or disease	Intervention/treatment	Phase
Hepatitis C; Pharmacokinetics	Drug: ribavirin (RBV); Drug: pegylated interferon (PegIFN) alfa-2a; Drug: BI 201335 NA low placebo; Drug: BI 201335 NA high; Drug: BI 201335 NA low; Drug: BI 201335 NA high placebo; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• 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
• Study Start Date: July 2009
• Actual Primary Completion Date: August 2011
• Actual Study Completion Date: August 2011

Arms and Interventions

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: pegylated interferon (PegIFN) alfa-2a; pegylated interferon (PegIFN) alfa-2a; Drug: BI 201335 NA low placebo; Placebo; Drug: ribavirin (RBV); ribavirin (RBV); 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: pegylated interferon (PegIFN) alfa-2a; pegylated interferon (PegIFN) alfa-2a; Drug: ribavirin (RBV); ribavirin (RBV); Drug: BI 201335 NA high; BI 201335 NA high
Placebo Comparator: Placebo in Treatment Naive (TN) Patients	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Investigator Defined Drug-related Adverse Events in Triple Combination Therapy [ Time Frame: 4 weeks ]
   Drug-related AEs were defined as those whose causal relationship with any one of the investigational products was considered by the investigator.
2. Number of Patients With Possible Clinically Significant Laboratory Abnormalities in Triple Combination Therapy [ Time Frame: 4 weeks ]
   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.
3. Assessment of Tolerability in Triple Combination Therapy [ Time Frame: 4 weeks ]
   An assessment of tolerability for the safety of the triple combination therapy with BI 201335 NA, PegIFN α -2a and RBV.

Secondary Outcome Measures :

1. Week 2 Virological Response (W2VR) [ Time Frame: 2 weeks ]
   Number of patients satisfying W2VR (plasma HCV RNA (Hepatitis C Virus Ribonucleic acid) level below the limit of quantification (BLQ))
2. Week 4 Virological Response (W4VR) [ Time Frame: 4 weeks ]
   Number of patients satisfying W4VR (plasma HCV RNA level below the limit of quantification (BLQ))
3. Rapid Virological Response (RVR) [ Time Frame: 4 weeks ]
   Number of patients satisfying RVR (plasma HCV RNA level below the limit of detection (BLD) at Week 4)
4. Change From Baseline in HCV Viral Load [ Time Frame: baseline and week 4 ]
   Change form baseline in HCV viral load (log10) after 4 weeks
5. Day 28 Virologic Response [ Time Frame: 4 weeks ]
   Number of patients with HCV viral load reduction >= 2 log10 at Week 4
6. Early Virological Response (EVR) [ Time Frame: 12 Weeks ]
   Number of patients with reduction >= 2 log10 in plasma HCV RNA level at Week 12
7. Complete Early Virological Response (cEVR) [ Time Frame: 12 weeks ]
   Number of patients with plasma HCV RNA level BLD at Week 12
8. End of Treatment Response (ETR) [ Time Frame: 48 weeks ]
   Number of patients with plasma HCV RNA level BLD at week 48
9. Sustained Virologic Response (SVR) [ Time Frame: 72 weeks ]
   Number of patients with plasma HCV RNA level BLD 24 weeks after treatment completion
10. Number of Participants With Investigator Defined Drug-related Adverse Events in Standard of Care (SOC) With PegIFN α-2a and RBV [ Time Frame: 44 weeks ]
    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.
11. Number of Patients With Possible Clinically Significant Laboratory Abnormalities in Standard of Care (SOC) With PegIFN α-2a and RBV [ Time Frame: 44 weeks ]
    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.
12. Assessment of Tolerability in Standard of Care (SOC) With PegIFN α -2a and RBV [ Time Frame: 44 weeks ]
    An assessment of tolerability for the safety of the SOC with PegIFN alfa-2a and RBV.
13. AUCτ,1 for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose ]
    Area under the curve (AUC) concentration after the first dose of BI 201335 ZW
14. Cmax of BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose ]
    Maximum concentration of BI 201335 ZW after multiple oral admin. of BI 201335 NA with RBV and PegIFN alfa-2a
15. AUCτ,ss of BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    AUC at steady state after 4 weeks combination of the last dose
16. Cmax,ss of BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    Maximum concentration of BI 201335 ZW at steady state
17. AUCτ,1 for Ribavirin (RBV) [ Time Frame: -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the first dose ]
    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
18. Cmax of RBV [ Time Frame: -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the first dose ]
    Maximum Plasma concentration of RBV after multiple oral admin. of placebo with RBV and PegIFN alfa-2a
19. AUCτ,ss of RBV [ Time Frame: -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the last dose ]
    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
20. Cmax,ss of RBV [ Time Frame: -0:10, 1,2,3,4,5,6,8,10,11:50, 23:50 hours on the last dose ]
    Maximum Plasma concentration of RBV after multiple oral admin. of BI 201335 NA (or placebo) with RBV and PegIFN alfa-2a at steady state
21. Tmax for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose ]
    Time to maximum plasma concentration (tmax) of BI 201335 ZW after the first dose of BI 201335 NA with RBV and PegIFN alfa-2a
22. Tmax for RBV [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the first dose ]
    Time to maximum plasma concentration (tmax) of RBV after the first dose of BI 201335 NA with RBV and PegIFN alfa-2a
23. Tmax, ss for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    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
24. Tmax, ss for RBV [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    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
25. t1/2,ss for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    terminal half-life of the analyte in plasma at steady state (t1/2,ss)
26. Cmin,ss for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    Minimum concentration of the analyte (BI 201335 ZW) in plasma over the dosing interval at steady state
27. Cmin,ss for RBV [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    Minimum concentration of the analyte (RBV) in plasma over the dosing interval at steady state
28. Cavg for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    average plasma concentration (Cavg) of BI 201335 ZW
29. Cavg for RBV [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    average plasma concentration (Cavg) of RBV
30. CL/F,ss for BI 201335 ZW [ Time Frame: 10 minutes before drug administration and 1 hour (h),2h,3h,4h,5h,6h,8h,10h,11:50h, 23:50h on the last dose ]
    apparent clearance of the analyte (BI 201335 ZW) in plasma at steady state (CL/F,ss) following multiple oral administration

Eligibility Criteria

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

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

Contacts and Locations

Locations

Japan

1220.14.003 Boehringer Ingelheim Investigational Site

Kurashiki, Okayama, Japan

1220.14.001 Boehringer Ingelheim Investigational Site

Minato-ku, Tokyo, Japan

1220.14.002 Boehringer Ingelheim Investigational Site

Nishinomiya, Hyogo, Japan

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00947349
• Other Study ID Numbers: 1220.14
• First Posted: July 28, 2009
• Results First Posted: July 7, 2015
• Last Update Posted: July 7, 2015
• Last Verified: July 2015

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Interferons; Ribavirin; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action