A Study of TMC435350 Administered With or Without Standard of Care Therapy in Participants With Genotype 1 Hepatitis C Virus Infection

• ClinicalTrials.gov Identifier: NCT00561353
• Recruitment Status: Completed
• First Posted: November 20, 2007
• Results First Posted: February 6, 2014
• Last Update Posted: May 20, 2014
• Sponsor: Tibotec Pharmaceuticals, Ireland
• Information provided by (Responsible Party): Tibotec Pharmaceuticals, Ireland

Study Description

Brief Summary:

The purpose of this study is to investigate how efficient TMC435350 will work against the Hepatitis C virus genotype 1 (genotypes refer to the genetic constitution of the virus) and what the concentrations of TMC435350 in the blood are with or without pegylated interferon alpha-2a (PegIFNa-2a) or PegIFNa-2a plus ribavirin.

Condition or disease	Intervention/treatment	Phase
Hepatitis C, Chronic	Drug: TMC435; Drug: Placebo; Drug: Peginterferon (PegIFNα-2a); Drug: Ribavirin	Phase 2

Detailed Description:

This is a blinded (participant and study staff will not know the identity of assigned treatments), randomized (participants assigned to treatment by chance), placebo-controlled (a term used to describe a method of research in which an inactive substance referred to as a placebo is given to one group of participants, while the treatment being tested is given to another group) study to assess the effectiveness, safety, tolerability, and pharmacokinetics (to test the concentration of study drug in the blood over time) of different dose regimens of TMC435350 (hereafter referred to as TMC435) given alone or in combination with peginterferon alpha-2a (PegIFNa-2a) and ribavirin. TMC435 is a new drug that is development for the treatment of Hepatitis C virus (HCV) infection and belongs to a class of drugs that work by blocking an enzyme (protease) that the HCV needs to replicate. The combination of PegIFNa-2a and ribavirin are current standard of care (SoC) therapy for patients with chronic HCV infection. Approximately 72 participants with HCV infection who have never been treated for HCV infection (referred to as treatment-naïve participants) and 36 participants who have been treated for HCV infection (referred to as treatment-experienced participants) who did not respond to previous therapy with interferon (IFN) and who did not discontinue previous anti-HCV therapy because of adverse events [AEs]) will be included in this study. Two blinded placebo-controlled groups (referred to as "cohorts") of treatment-naïve participants will be sequentially initiated TMC435 to ensure that a higher dose is only administered if the previous lower dose is found safe and tolerable. The first group (Cohort 1) of treatment-naïve participants will receive low-doses of TMC435 or placebo for 7 days followed by 21 days of combined tritherapy with PegIFNa-2a and ribavirin OR participants will receive 28 days of tritherapy (TMC435 or placebo + PegIFNa-2a and ribavirin). After review of data from Cohort 1, a second group (Cohort 2) of treatment-naïve participants will be given higher doses of TMC435 or placebo in the same manner described for the first cohort. A third group (Cohort 3) of participants previously planned in the study will not be enrolled. After review of data from Cohort 2, a fourth group (Cohort 4) of treatment-experienced participants will be given 28 days of TMC435 (or placebo) as tritherapy with PegIFNa-2a and ribavirin to determine the maximum tolerated dose of TMC435. In addition, up to 10 HCV-infected individuals (who participated in study TMC435350-TiDP16-C101 (ClinicalTrials.gov registry number NCT00938899) will comprise Cohort 5 and will be given 28 days of TMC435 at a dose previously determined to be safe and efficacious as tritherapy with PegIFNa-2a and ribavirin. Blood samples will be taken from participants at protocol-specified time points to determine plasma concentrations of TMC435 and ribavirin and safety will be monitored throughout the study. Individuals will participate in this study for up 54 weeks (includes up to 6 weeks during the screening period followed by up to 4 weeks of study treatment with TMC435 (or placebo) and up to a maximum of 44 weeks of treatment with PegIFNa-2a and ribavirin.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Blinded, Randomized, Placebo-controlled Trial in Genotype 1 Hepatitis C-Infected Subjects to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Repeated Doses of TMC435350, With or Without Peginterferon Alpha-2a and Ribavirin
• Study Start Date: January 2008
• Actual Primary Completion Date: December 2008
• Actual Study Completion Date: May 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: TMC435 25 mg (Cohort 1/Panel A and B); Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with peginterferon alpha-2a (PegIFNα-2a) (P) and ribavirin (R) for 21 days (Panel A) OR TMC435 25 mg once daily coadministered with PR for 28 days (Panel B).	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Experimental: TMC435 75mg (Cohort 1/Panel A and B); Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily for 21 days with PegIFNα-2a (P) and ribavirin (R) OR TMC435 75 mg once daily coadministered with PR for 28 days (Panel B).	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Placebo Comparator: Placebo (Cohort 1/Panel A and B); Treatment-naïve participants received placebo (identical in appearance to TMC435 25/75 mg) once daily for 7 days followed by placebo once daily coadministered with PegIFNα-2a (P) and ribavirin (R) for 21 days (Panel A) OR and Placebo once daily coadministered with PR for 28 days (Panel B).	Drug: Placebo; Placebo capsules identical in appearance to TMC435 capsules taken orally (by mouth) once daily for 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Experimental: TMC435 200 mg (Cohort 2, Panel A and B); Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with PegIFNα-2a (P) and ribavirin (R) for 21 days (Panel A) OR TMC435 200 mg once daily coadministered with PR for 28 days (Panel B).	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Placebo Comparator: Placebo (Cohort 2/Panel A and B); Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed by placebo once daily coadministered with PegIFNα-2a (P) and ribavirin (R) for 21 days (Panel A) OR placebo once daily coadministered with PR for 28 days (Panel B).	Drug: Placebo; Placebo capsules identical in appearance to TMC435 capsules taken orally (by mouth) once daily for 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Experimental: TMC435 75 mg (Cohort 4/Panel C); Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with PegIFNα-2a and ribavirin for 28 days.	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Experimental: TMC435 150 mg (Cohort 4/Panel C); Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with PegIFNα-2a and ribavirin for 28 days.	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Experimental: TMC435 200 mg (Cohort 4/Panel C); Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with PegIFNα-2a and ribavirin for 28 days.	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Placebo Comparator: Placebo (Cohort 4/Panel C); Treatment-experienced non-responders received placebo once daily coadministered with PegIFNα-2a and ribavirin for 28 days.	Drug: Placebo; Placebo capsules identical in appearance to TMC435 capsules taken orally (by mouth) once daily for 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS
Experimental: TMC435 200 mg (Cohort 5/Panel D); Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with PegIFNα-2a and ribavirin for 28 days.	Drug: TMC435; TMC435 25 mg, 75 mg, 150 mg, or 200 mg capsules taken orally (by mouth) once daily for 21 or 28 days.; Drug: Peginterferon (PegIFNα-2a); One subcutaneous (under the skin) injection containing 0.5 mL solution with 180 mcg PegIFNα-2a on Days 1, 8, 15, and 22; Other Name: PEGASYS; Drug: Ribavirin; 200-mg tablets of ribavirin (body-weight adjusted dose) taken orally (by mouth) twice daily for 21 or 28 days in Cohorts 1 and 2 and for 28 days in Cohorts 4 and 5.; Other Name: COPEGUS

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels (log10 IU/mL) at Week 4 in Treatment-Naïve HCV-Infected Participants (Cohort 1 and 2, Panel A) [ Time Frame: Week 4 ]
   The table below shows the change from Baseline in plasma levels of HCV RNA at Week 4 following treatment with TMC435 or placebo as for 7 days followed by TMC435 or placebo coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22 in treatment-naïve HCV-infected participants. (A treatment-naive participant is someone who has never taken drugs for their HCV infection).
2. Change From Baseline in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels (log10 IU/mL) at Week 4 in Treatment-Naïve HCV-Infected Participants (Cohort 1 and 2, Panel B) [ Time Frame: Week 4 ]
   The table below shows the change from Baseline in plasma levels of HCV RNA at Week 4 following treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22 in treatment-naïve HCV-infected participants. (A treatment-naive participant is someone who has never taken drugs for their HCV infection).
3. Change From Baseline in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels (log10 IU/mL) at Week 4 in Treatment-Experienced HCV-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Week 4 ]
   The table below shows the change from Baseline in plasma levels of HCV RNA at Week 4 following treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22 in treatment-experienced participants considered non-responders (defined as participants who achieved less than a 2 log10 IU/mL decline from baseline in plasma HCV RNA levels after 12 weeks of previous interferon [IFN]-based therapy [pegylated or non-pegylated]) or relapsers (defined as a participant with undetectable plasma HCV RNA at the end of treatment of previous IFN-based therapy and subsequent confirmed detectable plasma HCV RNA levels during follow-up).

Secondary Outcome Measures :

1. Change From Baseline in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels (log10 IU/mL) on Day 7 in Treatment-Naïve HCV-Infected Participants (Cohort 1 and 2, Panel A) [ Time Frame: Day 7 ]
   The table below shows the change from Baseline in plasma levels of HCV RNA on Day 7 (at Week 1) following treatment with TMC435 or placebo for 7 days followed by TMC435 or placebo coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 in treatment-naïve HCV-infected participants. (A treatment-naive participant is someone who has never taken drugs for their HCV infection).
2. Change From Baseline in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels (log10 IU/mL) on Day 7 in Treatment-Naïve HCV-Infected Participants (Cohort 1 and 2, Panel B) [ Time Frame: Day 7 ]
   The table below shows the change from Baseline in plasma levels of HCV RNA on Day 7 (at Week 1) following treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22 in treatment-naïve HCV-infected participants (A treatment-naive participant is someone who has never taken drugs for their HCV infection).
3. Change From Baseline in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels (log10 IU/mL) on Day 7 in Treatment-Experienced HCV-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Day 7 ]
   The table below shows the change from Baseline in plasma levels of HCV RNA on Day 7 (Week 1) following treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22 in treatment-experienced participants considered non-responders (defined as participants who achieved less than a 2 log10 IU/mL decline from baseline in plasma HCV RNA levels after 12 weeks of previous interferon [IFN]-based therapy [pegylated or non-pegylated]) or relapsers (defined as a participant with undetectable plasma HCV RNA at the end of treatment of previous IFN-based therapy and subsequent confirmed detectable plasma HCV RNA levels during follow-up).
4. Virologic Responses Following Treatment With TMC435 in Treatment-Naive Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A) [ Time Frame: Day 2 or 3, Day 7, and Day 28 ]
   The table below shows the number of treatment-naïve HCV-infected participants treated with TMC435 or placebo for 7 days followed by TMC435 or placebo coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 who had the following virologic responses: plasma levels of HCV ribonucleic acid (RNA) of greater than or equal to 2 log10 decline from Baseline; plasma levels of HCV RNA below the limit of quantification (ie, less than [<] 25 IU/mL detectable or undetectable); plasma levels of HCV RNA below the limit of detection (ie, <25 IU/mL undetectable); plasma levels of HCV RNA <100 IU/mL; and plasma levels of HCV RNA <1000 at the time points listed. See "treatment-naive" defined above.
5. Virologic Responses Following Treatment With TMC435 in Treatment-Naive Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel B) [ Time Frame: Day 2 or 3, Day 7, and Day 28 ]
   The table below shows the number of treatment-naive HCV-Infected participants with the following virologic responses to treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22: plasma levels of HCV ribonucleic acid (RNA) of greater than or equal to 2 log10 decline from Baseline; plasma levels of HCV RNA below the limit of quantification (ie, less than [<] 25 IU/mL detectable or undetectable); plasma levels of HCV RNA below the limit of detection (ie, <25 IU/mL undetectable); plasma levels of HCV RNA <100 IU/mL; and plasma levels of HCV RNA <1000 at the time points listed. See "treatment-naive" defined above.
6. Virologic Responses Following Treatment With TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Day 2 or 3, Day 7, and Day 28 ]
   The table below shows the number of treatment-experienced participants (non-responders and relapsers, see defined above) with the following virologic responses to treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22: plasma levels of HCV ribonucleic acid (RNA) of greater than or equal to 2 log10 decline from Baseline; plasma levels of HCV RNA below the limit of quantification (ie, less than [<] 25 IU/mL detectable or undetectable); plasma levels of HCV RNA below the limit of detection (ie, <25 IU/mL undetectable); plasma levels of HCV RNA <100 IU/mL; and plasma levels of HCV RNA <1000 at the time points listed. Note: in the table below, the number of participants (n) analyzed in the TMC435 200 mg (Cohort 4, Panel B) on Day 28 (Week 4) was n=4.
7. Virologic Response Parameters in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined) [ Time Frame: Week 4 (RVR), Week 12 (EVR, cEVR, and partial response), and Week 4 and 12 (eRVR) ]
   The table below shows the number of treatment-naïve participants in the treatment groups for Cohort 1 (Panel A and B combined) and in Cohort 2 (Panel A and B combined) who met the following virologic response parameters: rapid virological response (RVR) defined as having undetectable plasma HCV ribonucleic acid (RNA) at Week 4; early virologic response (EVR) defined as change from baseline in plasma HCV RNA of greater than or equal to 2 log 10 at Week 12); a complete EVR (cEVR) defined as a complete EVR having undetectable plasma HCV RNA at Week 12); an extended RVR (eRVR) defined as undetectable plasma HCV RNA at Week 4 and 12; and a partial response defined as EVR but not reaching undetectability while on treatment.
8. Virologic Response Parameters Following Treatment With TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Week 4 (RVR), Week 12 (EVR, cEVR, and partial response), and Week 4 and 12 (eRVR) ]
   The table below shows the number of treatment-experienced participants (non-responders and relapsers, see defined above) treated with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22 who met the following virologic response parameters: rapid virological response (RVR) defined as having undetectable plasma HCV ribonucleic acid (RNA) at Week 4; early virologic response (EVR) defined as change from baseline in plasma HCV RNA of greater than or equal to 2 log 10 at Week 12; a complete EVR (cEVR) defined as a EVR having undetectable plasma HCV RNA at Week 12; an extended RVR (eRVR) defined as undetectable plasma HCV RNA at Week 4 and 12; and a partial response defined as EVR but not reaching undetectability while on treatment.
9. Initial Suboptimal Responses Following Treatment With TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A) [ Time Frame: Day 2 or 3 ]
   The table below shows the number of treatment-naïve participants with an initial suboptimal response defined as less than 2 log10 change in plasma level of hepatitis C virus (HCV) ribonucleic acid (RNA) on Day 2 or 3 (depending when visit was scheduled) following treatment with TMC435 or placebo for 7 days followed by TMC435 or placebo coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. See "treatment-naive" defined above.
10. Initial Suboptimal Responses Following Treatment With TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel B) [ Time Frame: Day 2 or 3 ]
    The table below shows the number of treatment-naïve participants with an initial suboptimal response defined as less than 2 log10 change in plasma plasma level of hepatitis C virus (HCV) ribonucleic acid (RNA) on Day 2 or 3 (depending when visit was scheduled) after treatment with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. See "treatment-naive" defined above.
11. Initial Suboptimal Responses Following Treatment With TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Day 2 or 3 ]
    The table below shows the number of treatment-experienced participants (non-responders and relapsers, see defined above) with an initial suboptimal response defined as less than 2 log10 change of plasma in plasma level of HCV ribonucleic acid (RNA) at Day 2 or 3 (depending when visit was scheduled) treated with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22.
12. Viral Breakthrough in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1, Panel A and B) [ Time Frame: 4 Weeks (Wks), 44 Wks, and 48 Wks ]
    The table below shows the number of treatment-naïve participants with viral breakthrough, defined as a confirmed increase of greater than 1 log10 IU/mL in plasma HCV ribonucleic acid (RNA) level from the lowest level reached, or a confirmed plasma HCV RNA level of greater than 100 IU/mL in participants whose plasma HCV RNA had previously been below the limit of quantification (25 IU/mL detectable) or undetectable (less than 25 IU/mL undetectable) after treatment with TMC435 or placebo for 7 days followed by TMC435 or placebo coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on days 8, 15, and 22 (Panel A) and after treatment with TMC435 or placebo coadministered with ribavirin for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B).
13. Viral Breakthrough in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: 4 Weeks (Wks), 44 Wks, and 48 Wks ]
    The table below shows the number of treatment-experienced participants (non-responders and relapsers, see defined above) with viral breakthrough, defined as a confirmed increase of greater than 1 log10 IU/mL in plasma HCV ribonucleic acid (RNA) level from the lowest level reached), or a confirmed plasma HCV RNA level of greater than 100 IU/mL in participants whose plasma HCV RNA had previously been below the limit of quantification (25 IU/mL detectable) or undetectable (less than 25 IU/mL undetectable) treated with TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22.
14. Viral Relapse in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined) [ Time Frame: Up to Week 72 ]
    The table below shows the number of treatment-naïve participants with viral relapse (defined as having confirmed detectable plasma level of HCV ribonucleic acid [RNA] during the follow-up period in participants with undetectable plasma HCV RNA [less than 25 IU/mL undetectable] at the end of treatment) for the treatment groups in Cohort 1 (Panel A and B combined) and in Cohort 2 (Panel A and B combined). See "treatment-naïve" defined above.
15. Viral Relapse in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Up to Week 72 ]
    The table below shows the number of treatment-experienced participants combined (non-responders and relapsers, see defined above) with viral relapse, defined as having confirmed detectable plasma level of HCV ribonucleic acid (RNA) during the follow-up period in participants with undetectable plasma HCV RNA (less than 25 IU/mL undetectable) at the end of treatment who received TMC435 or placebo coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22.
16. Sustained Virologic Response (SVR) in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined) [ Time Frame: SVR4 (Week 52), SVR8 (Week 56), SVR12 (Week 60), and SVR24 (Week 72) ]
    The table below shows the number of treatment-naïve participants with an SVR to treatment (defined as having an undetectable plasma level of HCV ribonucleic acid after the last planned dose of treatment) for the treatment groups in Cohort 1 (Panel A and B combined) and in Cohort 2 (Panel A and B combined). SVR was measured at 4, 8, 12, and 24 weeks after the last dose of treatment (SVR4, SVR8, SVR12, and SVR24, respectively). See "treatment-naïve" defined above.
17. Sustained Virologic Response (SVR) in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: SVR4 (Week 52), SVR8 (Week 56), SVR12 (Week 60), and SVR24 (Week 72) ]
    The table below shows the number of treatment-experienced participants (non-responders and relapsers, see defined above) in each treatment group in Cohort 4, Panel C and in Cohort 5, Panel D with an SVR to treatment defined as having an undetectable plasma level of HCV ribonucleic acid after the last planned dose of the entire treatment regimen. SVR was measured at 4, 8, 12, and 24 weeks after the last dose of treatment (SVR4, SVR8, SVR12, and SVR24, respectively).
18. Maximum Plasma Concentration (Cmax) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B) [ Time Frame: Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows the mean (standard deviation) Cmax for treatment-naïve participants at selected time points who were treated with TMC435 for 7 days followed by TMC435 coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) and with TMC435 coadministered with ribavirin for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). See "treatment-naïve" defined above. The number of participants analyzed at Day 28 in the 6 treatment groups listed below from left to right were 9, 8, 7, 9, 9, and 10.
19. Maximum Plasma Concentration (Cmax) of TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows the mean (standard deviation) Cmax for treatment-experienced participants (non-responders and relapsers, see defined above) following treatment with TMC435 coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. The number of participants analyzed at Day 28 in the 4 treatment groups listed below from left to right were 8, 8, 10, and 3.
20. Predose Plasma Concentration (C0h) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B) [ Time Frame: Day 2 (predose) and Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows mean (standard deviation) of C0h of TMC435 at selected time points following treatment with TMC435 for 7 days followed by TMC435 coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) or with TMC435 coadministered with ribavirin for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) in treatment-naïve participants (see "treatment-naïve" defined above).The number of participants analyzed at Day 28 in the 6 treatment groups listed below from left to right were 9, 9, 8, 9, 9, and 10.
21. Predose Plasma Concentration (C0h) of TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Day 2 (predose) and Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows mean (standard deviation) of C0h for treatment-experienced participants (non-responders and relapsers, see defined above) following treatment with TMC435 coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. The number of participants analyzed at Day 2 and Day 28 differed as follows: At Day 2, the number of participants in the 4 treatment groups (from left to right) were 8, 7, 10, and 5; the number of participants analyzed at Day 28 in the 4 treatment groups (from left to right) were 9, 8, 10, and 4.
22. Average Steady-state Plasma Concentration (Css,av) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B) [ Time Frame: Day 7 (predose); Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) (Panel A, Cohorts 1 and 2) and Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) (Panel B, Cohorts 1 and 2) ]
    The table below shows mean (standard deviation)of Css,av for TMC435 in treatment-naïve HCV-infected participants at selected time points administered TMC435 for 7 days followed by TMC435 coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) and with TMC435 coadministered with ribavirin for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). See "treatment-naïve" defined above. The number of participants analyzed at Day 28 in the 6 treatment groups listed below from left to right were 9, 8, 7, 9, 9, and 10.
23. Average Steady-state Plasma Concentration (Css,av) of TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows mean (standard deviation) of Css,av for TMC435 in treatment-experienced HCV-infected participants (non-responders and relapsers, see defined above) at selected time points following treatment with TMC435 coadministered with ribavirin for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22.
24. Area Under the Plasma Concentration-time Curve From the Time of Administration to 24 Hours After Dosing (AUC24h) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B) [ Time Frame: Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows mean (standard deviation) values of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing for TMC435 in treatment-naïve HCV-infected participants administered TMC435 for 7 days followed by TMC435 coadministered with ribavirin for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) and with TMC435 coadministered with ribavirin for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B).The number of participants analyzed at Day 28 in the 6 treatment groups listed below from left to right were 9, 8, 7, 9, 9, and 10.
25. Area Under the Plasma Concentration-time Curve From the Time of Administration to 24 Hours After Dosing (AUC24h) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D) [ Time Frame: Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose) ]
    The table below shows mean (standard deviation) values of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing for TMC435 in treatment-experienced HCV-infected participants considered non-responders (participants who achieved less than a 2 log10 IU/mL decline from baseline in plasma HCV ribonucleic acid (RNA) levels after 12 weeks of previous interferon [IFN]-based therapy [pegylated or non-pegylated]) or relapsers (defined as a participant with undetectable plasma HCV RNA at the end of treatment of previous IFN-based therapy and subsequent confirmed detectable plasma HCV RNA levels during follow-up at selected time points following treatment with TMC435 coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. The number of participants analyzed at Day 28 in the 4 treatment groups listed below from left to right was 8, 7, 10, and 3.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria: - Documented chronic genotype 1 Hepatitis C infection - Able to comply with the protocol requirements and having good accessible veins - Amount of virus in the blood (HCV RNA) >= 10.000 IU/mL, at screening - Bodyweight as defined by a Quetelet Index (Body Mass Index [BMI]) between 18 and 32 kg/m², extremes included Exclusion Criteria: - Evidence of liver cirrhosis or decompensated liver disease or any other form of non-viral hepatitis - Participants receiving or having received treatment with polymerase inhibitor or protease inhibitor, or Standard of Care therapy with COPEGUS (ribavirin) and PEGASYS (peginterferon alpha-2a) for treatment for HCV during the 6 months before screening - Male participants with female partners of childbearing potential not agreeing to use a reliable birth control method, Female, except if postmenopausal for over 2 years, or posthysterectomy, or post-tubal ligation (without reversal operation) - History or evidence of current use of alcohol, barbiturate, amphetamine, recreational or narcotic drug use, which would compromise the participant 's safety and/or compliance. A positive urine drug test at screening. Urine will be tested to check the current use of amphetamines, cocaine, and opioids (with the exclusion of methadone) - Participants having at least one lab toxicity that is found to be clinically significant - Participants co-infected with HIV, or Hepatitis A or B, or hepatitis B surface antigen, or active tuberculosis at screening, participants with prolonged QTc (>480 ms) value or any cardiac disease at screening, or any active clinically significant disease (e.g., cardiac dysfunction, cardio(myo)pathy, cardiac insufficiency), or medical history or physical examination findings during screening that, in the Investigator's opinion, would compromise the outcome of the trial - Participants having uncontrolled/unstable diabetes, epilepsy, a manifest psychiatric disease, non-stable methadone (or equivalent drug) use or participants having any other unstable disease, participants enrolled in another clinical trial within 90 days prior to screening

Contacts and Locations

Locations

Belgium

Brugge, Belgium

Brussels, Belgium

Bruxelles, Belgium

Edegem, Belgium

Gent, Belgium

France

Clichy, France

Lyon, France

Marseille, France

Paris Cedex 10, France

Paris, France

Pessac, France

Vandoeuvre Les Nancy, France

Germany

Berlin, Germany

Düsseldorf, Germany

Freiburg, Germany

Hamburg, Germany

Hannover, Germany

Kiel, Germany

Munchen, Germany

Netherlands

Amsterdam Zuidoost, Netherlands

Poland

Bialystok, Poland

Kielce, Poland

Lodz, Poland

Warszawa, Poland

United Kingdom

London, United Kingdom

Plymouth, United Kingdom

Sponsors and Collaborators

Tibotec Pharmaceuticals, Ireland

Investigators

• Study Director: Tibotec Pharmaceuticals, Ireland Clinical Trial; Tibotec Pharmaceuticals, Ireland

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lenz O, de Bruijne J, Vijgen L, Verbinnen T, Weegink C, Van Marck H, Vandenbroucke I, Peeters M, Simmen K, Fanning G, Verloes R, Picchio G, Reesink H. Efficacy of re-treatment with TMC435 as combination therapy in hepatitis C virus-infected patients following TMC435 monotherapy. Gastroenterology. 2012 Nov;143(5):1176-1178.e6. doi: 10.1053/j.gastro.2012.07.117. Epub 2012 Aug 8.

Manns M, Reesink H, Berg T, Dusheiko G, Flisiak R, Marcellin P, Moreno C, Lenz O, Meyvisch P, Peeters M, Sekar V, Simmen K, Verloes R. Rapid viral response of once-daily TMC435 plus pegylated interferon/ribavirin in hepatitis C genotype-1 patients: a randomized trial. Antivir Ther. 2011;16(7):1021-33. doi: 10.3851/IMP1894.

• Responsible Party: Tibotec Pharmaceuticals, Ireland
• ClinicalTrials.gov Identifier: NCT00561353
• Obsolete Identifiers: NCT00614185
• Other Study ID Numbers: CR012607; TMC435350-TiDP16-C201 ( Other Identifier: Tibotec Pharmaceuticals, Ireland )
• First Posted: November 20, 2007
• Results First Posted: February 6, 2014
• Last Update Posted: May 20, 2014
• Last Verified: May 2014

Keywords provided by Tibotec Pharmaceuticals, Ireland:

Hepatitis C, Chronic; Tibotec; TMC435350-TiDP16-C201; TMC435350-C201; TMC435; PEGASYS (peginterferon alpha-2a, PegIFNα-2a); COPEGUS (ribavirin)

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis C, Chronic; 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; Hepatitis, Chronic; Ribavirin; Simeprevir; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents; Protease Inhibitors; Enzyme Inhibitors