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

Sponsor
Tibotec Pharmaceuticals, Ireland (Industry)
Overall Status
Completed
CT.gov ID
NCT00561353
Collaborator
(none)
121
Enrollment
26
Locations
10
Arms
28
Duration (Months)
4.7
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

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
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
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 :
Jan 1, 2008
Actual Primary Completion Date :
Dec 1, 2008
Actual Study Completion Date :
May 1, 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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 Names:
  • 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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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

    Criteria

    Ages Eligible for Study:
    18 Years to 70 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    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

    Site City State Country Postal Code
    1 Brugge Belgium
    2 Brussels Belgium
    3 Bruxelles Belgium
    4 Edegem Belgium
    5 Gent Belgium
    6 Clichy France
    7 Lyon France
    8 Marseille France
    9 Paris Cedex 10 France
    10 Paris France
    11 Pessac France
    12 Vandoeuvre Les Nancy France
    13 Berlin Germany
    14 Düsseldorf Germany
    15 Freiburg Germany
    16 Hamburg Germany
    17 Hannover Germany
    18 Kiel Germany
    19 Munchen Germany
    20 Amsterdam Zuidoost Netherlands
    21 Bialystok Poland
    22 Kielce Poland
    23 Lodz Poland
    24 Warszawa Poland
    25 London United Kingdom
    26 Plymouth United Kingdom

    Sponsors and Collaborators

    • Tibotec Pharmaceuticals, Ireland

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Tibotec Pharmaceuticals, Ireland
    ClinicalTrials.gov Identifier:
    NCT00561353
    Other Study ID Numbers:
    • CR012607
    • TMC435350-TiDP16-C201
    • NCT00614185
    First Posted:
    Nov 20, 2007
    Last Update Posted:
    May 20, 2014
    Last Verified:
    May 1, 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
    Ribavirin
    Simeprevir

    Study Results

    Participant Flow

    Recruitment Details The study was conducted at 25 sites in 6 countries: Belgium, France, Germany, Poland, the Netherlands, and the United Kingdom.
    Pre-assignment Detail A total of 121 participants infected with Hepatitis C virus (HCV) were randomized of whom 116 were treated. Reasons for not receiving treatment were withdrawal of consent (4 participants) and sponsor's decision (1 participant).
    Arm/Group Title TMC435 25 mg (Cohort 1/Panel A and B) TMC435 75mg (Cohort 1/Panel A and B) Placebo (Cohort 1/Panel A and B) TMC435 200 mg (Cohort 2, Panel A and B) Placebo (Cohort 2/Panel A and B) TMC435 75 mg (Cohort 4/Panel C) TMC435 150 mg (Cohort 4/Panel C) TMC435 200 mg (Cohort 4/Panel C) Placebo (Cohort 4/Panel C) TMC435 200 mg (Cohort 5/Panel D)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel 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 RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Period Title: Overall Study
    STARTED 18 19 13 18 6 9 9 10 9 5
    COMPLETED 13 16 10 12 5 3 3 6 2 3
    NOT COMPLETED 5 3 3 6 1 6 6 4 7 2

    Baseline Characteristics

    Arm/Group Title TMC435 25 mg (Cohort 1) TMC435 75mg (Cohort 1) Placebo (Cohort 1) TMC435 200 mg (Cohort 2) Placebo (Cohort 2) TMC435 75 mg (Cohort 4) TMC435 150 mg (Cohort 4) TMC435 200 mg (Cohort 4) Placebo (Cohort 4) TMC435 200 mg (Cohort 5) Total
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel 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 RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Total of all reporting groups
    Overall Participants 18 19 13 18 6 9 9 10 9 5 116
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    52
    47
    45
    46.5
    44.5
    53
    56
    55.5
    47
    56
    49
    Sex: Female, Male (Count of Participants)
    Female
    5
    27.8%
    8
    42.1%
    3
    23.1%
    8
    44.4%
    1
    16.7%
    3
    33.3%
    1
    11.1%
    2
    20%
    0
    0%
    0
    0%
    31
    26.7%
    Male
    13
    72.2%
    11
    57.9%
    10
    76.9%
    10
    55.6%
    5
    83.3%
    6
    66.7%
    8
    88.9%
    8
    80%
    9
    100%
    5
    100%
    85
    73.3%
    The Number of Participants Randomized to each Treatment Panel (participants) [Number]
    Panel A
    9
    50%
    10
    52.6%
    6
    46.2%
    9
    50%
    3
    50%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    37
    31.9%
    Panel B
    9
    50%
    9
    47.4%
    7
    53.8%
    9
    50%
    3
    50%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    37
    31.9%
    Panel C
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    9
    100%
    9
    100%
    10
    100%
    9
    100%
    0
    0%
    37
    31.9%
    Panel D
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    5
    100%
    5
    4.3%

    Outcome Measures

    1. Primary Outcome
    Title 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)
    Description 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).
    Time Frame Week 4

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) Placebo (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) Placebo (Cohort 2, Panel A)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22.
    Measure Participants 9 10 6 9 3
    Mean (Standard Error) [log10 IU/mL]
    -4.26
    (0.646)
    -4.47
    (0.489)
    -2.97
    (0.640)
    -4.70
    (0.584)
    -1.92
    (0.156)
    2. Primary Outcome
    Title 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)
    Description 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).
    Time Frame Week 4

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) Placebo (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B) Placebo (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 7 9 3
    Mean (Standard Error) [log10 IU/mL]
    -4.74
    (0.455)
    -5.52
    (0.228)
    -3.74
    (0.665)
    -5.44
    (0.169)
    -3.26
    (1.222)
    3. Primary Outcome
    Title 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)
    Description 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).
    Time Frame Week 4

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 4
    Mean (Standard Error) [log10 IU/mL]
    -4.28
    (0.539)
    -5.46
    (0.425)
    -5.26
    (0.238)
    -1.53
    (0.216)
    -5.86
    (0.198)
    4. Secondary Outcome
    Title 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)
    Description 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).
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) Placebo (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) Placebo (Cohort 2, Panel A)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants in received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22.
    Measure Participants 9 10 6 9 3
    Mean (Standard Error) [log10 IU/mL]
    -2.63
    (0.377)
    -3.48
    (0.285)
    -0.08
    (0.101)
    -4.18
    (0.158)
    0.30
    (0.080)
    5. Secondary Outcome
    Title 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)
    Description 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).
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) Placebo (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B) Placebo (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 28 days coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 7 9 3
    Mean (Standard Error) [log10 IU/mL]
    -3.47
    (0.500)
    -4.55
    (0.192)
    -1.73
    (0.441)
    -4.68
    (0.135)
    -1.64
    (0.793)
    6. Secondary Outcome
    Title 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)
    Description 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).
    Time Frame Day 7

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 5
    Mean (Standard Error) [log10 IU/mL]
    -3.80
    (0.432)
    -4.68
    (0.224)
    -4.49
    (0.318)
    -0.50
    (0.152)
    -4.08
    (0.387)
    7. Secondary Outcome
    Title Virologic Responses Following Treatment With TMC435 in Treatment-Naive Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A)
    Description 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.
    Time Frame Day 2 or 3, Day 7, and Day 28

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) Placebo (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) Placebo (Cohort 2, Panel A)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants in received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22.
    Measure Participants 9 10 6 9 3
    Day 2/3: > or = 2 log10 change from baseline
    6
    (0.646) 33.3%
    9
    (0.489) 47.4%
    0
    (0.640) 0%
    9
    (0.584) 50%
    0
    (0.156) 0%
    Day 7: > or = 2 log10 change from baseline
    7
    38.9%
    9
    47.4%
    0
    0%
    9
    50%
    0
    0%
    Day 28: > or = 2 log10 change from baseline
    7
    38.9%
    9
    47.4%
    4
    30.8%
    8
    44.4%
    1
    16.7%
    Day 2/3: <25 IU/mL detectable or undetectable
    1
    5.6%
    1
    5.3%
    0
    0%
    1
    5.6%
    0
    0%
    Day 7: <25 IU/mL detectable or undetectable
    1
    5.6%
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    Day 28: <25 IU/mL detectable or undetectable
    5
    27.8%
    8
    42.1%
    1
    7.7%
    7
    38.9%
    0
    0%
    Day 2/3: <25 IU/mL undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 7: <25 IU/mL undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 28: <25 IU/mL undetectable
    5
    27.8%
    5
    26.3%
    1
    7.7%
    7
    38.9%
    0
    0%
    Day 2/3: <100 IU/mL
    1
    5.6%
    1
    5.3%
    0
    0%
    1
    5.6%
    0
    0%
    Day 7: <100 IU/mL
    1
    5.6%
    3
    15.8%
    0
    0%
    4
    22.2%
    0
    0%
    Day 28: <100 IU/mL
    6
    33.3%
    8
    42.1%
    1
    7.7%
    7
    38.9%
    0
    0%
    Day 2/3: <1000 IU/mL
    2
    11.1%
    5
    26.3%
    0
    0%
    6
    33.3%
    0
    0%
    Day 7: <1000 IU/mL
    3
    16.7%
    6
    31.6%
    0
    0%
    7
    38.9%
    0
    0%
    Day 28: <1000 IU/mL
    7
    38.9%
    8
    42.1%
    2
    15.4%
    7
    38.9%
    0
    0%
    8. Secondary Outcome
    Title Virologic Responses Following Treatment With TMC435 in Treatment-Naive Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel B)
    Description 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.
    Time Frame Day 2 or 3, Day 7, and Day 28

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) Placebo (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B) Placebo (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg and 75 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 7 9 3
    Day 2/3: > or = 2 log10 change from baseline
    7
    (0.646) 38.9%
    9
    (0.489) 47.4%
    2
    (0.640) 15.4%
    9
    (0.584) 50%
    2
    (0.156) 33.3%
    Day 7: > or = 2 log10 change from baseline
    7
    38.9%
    9
    47.4%
    2
    15.4%
    9
    50%
    1
    16.7%
    Day 28: > or = 2 log10 change from baseline
    8
    44.4%
    9
    47.4%
    6
    46.2%
    9
    50%
    2
    33.3%
    Day 2/3: <25 IU/mL detectable or undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 7: <25 IU/mL detectable or undetectable
    1
    5.6%
    1
    5.3%
    0
    0%
    3
    16.7%
    0
    0%
    Day 28: <25 IU/mL detectable or undetectable
    6
    33.3%
    9
    47.4%
    3
    23.1%
    9
    50%
    1
    16.7%
    Day 2/3: <25 IU/mL undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 7: <25 IU/mL undetectable
    0
    0%
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    Day 28: <25 IU/mL undetectable
    3
    16.7%
    8
    42.1%
    2
    15.4%
    6
    33.3%
    0
    0%
    Day 2/3: <100 IU/mL
    0
    0%
    1
    5.3%
    0
    0%
    1
    5.6%
    0
    0%
    Day 7: <100 IU/mL
    1
    5.6%
    6
    31.6%
    0
    0%
    5
    27.8%
    0
    0%
    Day 28: <100 IU/mL
    6
    33.3%
    9
    47.4%
    3
    23.1%
    9
    50%
    1
    16.7%
    Day 2/3: <1000 IU/mL
    4
    22.2%
    5
    26.3%
    0
    0%
    6
    33.3%
    0
    0%
    Day 7: <1000 IU/mL
    5
    27.8%
    9
    47.4%
    0
    0%
    9
    50%
    0
    0%
    Day 28: <1000 IU/mL
    7
    38.9%
    9
    47.4%
    4
    30.8%
    9
    50%
    2
    33.3%
    9. Secondary Outcome
    Title Virologic Responses Following Treatment With TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D)
    Description 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.
    Time Frame Day 2 or 3, Day 7, and Day 28

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 5
    Day 2/3: > or = 2 log10 change from baseline
    8
    (0.646) 44.4%
    9
    (0.489) 47.4%
    10
    (0.640) 76.9%
    1
    (0.584) 5.6%
    4
    (0.156) 66.7%
    Day 7: > or = 2 log10 change from baseline
    8
    44.4%
    9
    47.4%
    10
    76.9%
    0
    0%
    5
    83.3%
    Day 28: > or = 2 log10 change from baseline
    8
    44.4%
    9
    47.4%
    10
    76.9%
    2
    11.1%
    4
    66.7%
    Day 2/3: <25 IU/mL detectable or undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 7: <25 IU/mL detectable or undetectable
    0
    0%
    2
    10.5%
    3
    23.1%
    0
    0%
    0
    0%
    Day 28: <25 IU/mL detectable or undetectable
    4
    22.2%
    7
    36.8%
    7
    53.8%
    0
    0%
    4
    66.7%
    Day 2/3: <25 IU/mL undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 7: <25 IU/mL undetectable
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 28: <25 IU/mL undetectable
    2
    11.1%
    5
    26.3%
    3
    23.1%
    0
    0%
    3
    50%
    Day 2/3: <100 IU/mL
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Day 7: <100 IU/mL
    2
    11.1%
    4
    21.1%
    5
    38.5%
    0
    0%
    0
    0%
    Day 28: <100 IU/mL
    6
    33.3%
    8
    42.1%
    7
    53.8%
    0
    0%
    4
    66.7%
    Day 2/3: <1000 IU/mL
    3
    16.7%
    3
    15.8%
    5
    38.5%
    0
    0%
    0
    0%
    Day 7: <1000 IU/mL
    5
    27.8%
    7
    36.8%
    8
    61.5%
    0
    0%
    3
    50%
    Day 28: <1000 IU/mL
    6
    33.3%
    8
    42.1%
    10
    76.9%
    0
    0%
    4
    66.7%
    10. Secondary Outcome
    Title Virologic Response Parameters in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined)
    Description 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.
    Time Frame Week 4 (RVR), Week 12 (EVR, cEVR, and partial response), and Week 4 and 12 (eRVR)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A and B) TMC435 75mg (Cohort 1, Panel A and B) Placebo (Cohort 1, Panel A and B) TMC435 200mg (Cohort 2, Panel A and B) Placebo (Cohort 2, Panel A and B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B).
    Measure Participants 18 19 13 18 6
    RVR
    8
    (0.646) 44.4%
    13
    (0.489) 68.4%
    3
    (0.640) 23.1%
    13
    (0.584) 72.2%
    0
    (0.156) 0%
    EVR
    16
    88.9%
    19
    100%
    12
    92.3%
    16
    88.9%
    6
    100%
    cEVR
    13
    72.2%
    17
    89.5%
    7
    53.8%
    16
    88.9%
    5
    83.3%
    eRVR
    8
    44.4%
    13
    68.4%
    3
    23.1%
    13
    72.2%
    0
    0%
    Partial response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    16.7%
    11. Secondary Outcome
    Title 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)
    Description 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.
    Time Frame Week 4 (RVR), Week 12 (EVR, cEVR, and partial response), and Week 4 and 12 (eRVR)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 5
    RVR
    2
    (0.646) 11.1%
    5
    (0.489) 26.3%
    3
    (0.640) 23.1%
    0
    (0.584) 0%
    3
    (0.156) 50%
    EVR
    6
    33.3%
    7
    36.8%
    8
    61.5%
    8
    44.4%
    4
    66.7%
    cEVR
    4
    22.2%
    4
    21.1%
    5
    38.5%
    0
    0%
    3
    50%
    eRVR
    2
    11.1%
    4
    21.1%
    3
    23.1%
    0
    0%
    3
    50%
    Partial response
    0
    0%
    1
    5.3%
    1
    7.7%
    5
    27.8%
    0
    0%
    12. Secondary Outcome
    Title Initial Suboptimal Responses Following Treatment With TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A)
    Description 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.
    Time Frame Day 2 or 3

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) Placebo (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) Placebo (Cohort 2, Panel A)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received placebo identical in appearance toTMC435 25 or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22.
    Measure Participants 9 10 6 9 3
    Number [Participants]
    3
    16.7%
    1
    5.3%
    6
    46.2%
    0
    0%
    3
    50%
    13. Secondary Outcome
    Title Initial Suboptimal Responses Following Treatment With TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel B)
    Description 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.
    Time Frame Day 2 or 3

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat (ITT) population, defined as all participants who were randomized and received at least one dose of study medication (TMC435) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) Placebo (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B) Placebo (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 28 days coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 7 9 3
    Number [Participants]
    2
    (0.646) 11.1%
    0
    (0.489) 0%
    5
    (0.640) 38.5%
    0
    (0.584) 0%
    1
    (0.156) 16.7%
    14. Secondary Outcome
    Title 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)
    Description 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.
    Time Frame Day 2 or 3

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 5
    Number [Participants]
    1
    5.6%
    0
    0%
    0
    0%
    8
    44.4%
    1
    16.7%
    15. Secondary Outcome
    Title Viral Breakthrough in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1, Panel A and B)
    Description 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).
    Time Frame 4 Weeks (Wks), 44 Wks, and 48 Wks

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses. Note: Number of participants analyzed during the PegIFNα-2a and ribavirin treatment period of up to 44 weeks is N=16 for TMC435 25 mg, N=17 for TMC435 75 mg, and N=17 for TMC435 200 mg.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panels A and B) TMC435 75 mg (Cohort 1, Panels A and B) Placebo (Cohort 1, Panels A and B) TMC435 200 mg (Cohort 2, Panels A and B) Placebo (Cohort 2, Panels A and B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B).
    Measure Participants 18 19 13 18 6
    Entire treatment period (48 Wks)
    3
    16.7%
    3
    15.8%
    0
    0%
    4
    22.2%
    0
    0%
    During TMC435/Placebo treatment (4 Wks)
    2
    11.1%
    2
    10.5%
    0
    0%
    1
    5.6%
    0
    0%
    During treatment with RBV and PegIFNα-2a (44 Wks)
    1
    5.6%
    1
    5.3%
    0
    0%
    3
    16.7%
    0
    0%
    16. Secondary Outcome
    Title Viral Breakthrough in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D)
    Description 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.
    Time Frame 4 Weeks (Wks), 44 Wks, and 48 Wks

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (TMC435 75/150/200 mg) (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received Placebo identical in appearance to TMC435 75 mg, 150 mg, or 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 5
    Entire treatment period (48 Wks)
    3
    16.7%
    4
    21.1%
    4
    30.8%
    1
    5.6%
    1
    16.7%
    During TMC435/Placebo treatment (4 Wks)
    2
    11.1%
    1
    5.3%
    0
    0%
    1
    5.6%
    0
    0%
    During treatment with RBV and PegIFNα-2a (44 Wks)
    1
    5.6%
    3
    15.8%
    4
    30.8%
    0
    0%
    1
    16.7%
    17. Secondary Outcome
    Title Viral Relapse in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined)
    Description 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.
    Time Frame Up to Week 72

    Outcome Measure Data

    Analysis Population Description
    The analysis population used to evaluate viral relapse included participants in the intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) who were treatment-naïve and had undetectable plasma HCV RNA (less than 25 IU/mL undetectable) at the end of treatment.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A and B) TMC435 75 mg (Cohort 1, Panel A and B) Placebo (Cohort 1, Panel A and B) TMC435 200 mg (Cohort 2, Panel A and B) Placebo (Cohort 2, Panel A and B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed by Placebo once daily coadministered with RBV for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B).
    Measure Participants 15 18 12 14 5
    Relapse
    2
    11.1%
    1
    5.3%
    2
    15.4%
    1
    5.6%
    0
    0%
    No relapse
    12
    66.7%
    17
    89.5%
    10
    76.9%
    13
    72.2%
    5
    83.3%
    Missing follow-up
    1
    5.6%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    18. Secondary Outcome
    Title Viral Relapse in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D)
    Description 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.
    Time Frame Up to Week 72

    Outcome Measure Data

    Analysis Population Description
    The analysis population used to evaluate viral relapse included participants in the intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) who were treatment-experienced and had undetectable plasma HCV RNA (less than 25 IU/mL undetectable) at the end of treatment.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (TMC435 75/150/200 mg) (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received Placebo identical in appearance to TMC435 75 mg, 150 mg, or 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers in Cohort 5, Panel D received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 6 3 6 3 3
    Relapse
    3
    16.7%
    0
    0%
    1
    7.7%
    3
    16.7%
    0
    0%
    No relapse
    3
    16.7%
    3
    15.8%
    5
    38.5%
    0
    0%
    3
    50%
    19. Secondary Outcome
    Title Sustained Virologic Response (SVR) in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined)
    Description 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.
    Time Frame SVR4 (Week 52), SVR8 (Week 56), SVR12 (Week 60), and SVR24 (Week 72)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A and B) TMC435 75mg (Cohort 1, Panel A and B) Placebo (Cohort 1, Panel A and B) TMC435 200mg (Cohort 2, Panel A and B) Placebo (Cohort 2, Panel A and B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed by Placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B). Treatment-naïve participants received placebo (identical in appearance to TMC435 200 mg) once daily for 7 days followed RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B).
    Measure Participants 18 19 13 18 6
    SVR4
    12
    66.7%
    16
    84.2%
    11
    84.6%
    12
    66.7%
    5
    83.3%
    SVR8
    12
    66.7%
    14
    73.7%
    9
    69.2%
    12
    66.7%
    5
    83.3%
    SVR12
    12
    66.7%
    15
    78.9%
    9
    69.2%
    12
    66.7%
    5
    83.3%
    SVR24
    10
    55.6%
    15
    78.9%
    9
    69.2%
    12
    66.7%
    5
    83.3%
    20. Secondary Outcome
    Title Sustained Virologic Response (SVR) in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D)
    Description 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).
    Time Frame SVR4 (Week 52), SVR8 (Week 56), SVR12 (Week 60), and SVR24 (Week 72)

    Outcome Measure Data

    Analysis Population Description
    The intent-to-treat population (defined as all participants who were randomized and received at least one dose of study medication) was used for all analyses.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) Placebo (TMC435 75/150/200 mg) (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received Placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 10 9 5
    SVR4
    2
    11.1%
    3
    15.8%
    4
    30.8%
    1
    5.6%
    3
    50%
    SVR8
    1
    5.6%
    3
    15.8%
    4
    30.8%
    0
    0%
    3
    50%
    SVR12
    1
    5.6%
    3
    15.8%
    5
    38.5%
    0
    0%
    3
    50%
    SVR24
    1
    5.6%
    3
    15.8%
    5
    38.5%
    0
    0%
    3
    50%
    21. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B)
    Description 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.
    Time Frame Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 10 8 9 8 10
    Day 1
    251.1
    (77.40)
    1008
    (490.9)
    3369
    (1760)
    239.6
    (125.8)
    958.0
    (448.9)
    3945
    (2096)
    Day 28
    307.1
    (88.16)
    1058
    (547.5)
    11180
    (8522)
    329.4
    (186.9)
    1609
    (1310)
    10900
    (6974)
    22. Secondary Outcome
    Title Maximum Plasma Concentration (Cmax) of TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D)
    Description 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.
    Time Frame Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 9 4
    Day 1
    882.1
    (273.2)
    2422
    (919.0)
    2877
    (1399)
    3870
    (565.0)
    Day 28
    1481
    (879.6)
    4383
    (2374)
    8452
    (6112)
    12220
    (2917)
    23. Secondary Outcome
    Title Predose Plasma Concentration (C0h) of TMC435 in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B)
    Description 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.
    Time Frame Day 2 (predose) and Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 25 mg coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 28 days coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 8 9 8 9 9 10
    Day 2
    64.51
    (37.57)
    209.3
    (107.4)
    1053
    (526.5)
    65.73
    (41.75)
    281.6
    (288.1)
    821.7
    (422.9)
    Day 28
    64.78
    (35.15)
    331.6
    (326.6)
    6913
    (7726)
    95.83
    (61.56)
    632.8
    (1128)
    4818
    (5071)
    24. Secondary Outcome
    Title Predose Plasma Concentration (C0h) of TMC435 in Treatment-Experienced Hepatitis C Virus (HCV)-Infected Participants (Cohort 4, Panel C and Cohort 5, Panel D)
    Description 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.
    Time Frame Day 2 (predose) and Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 8 10 5
    Day 2
    278.4
    (192.2)
    733.6
    (436.4)
    669.8
    (301.7)
    1280
    (955.8)
    Day 28
    324.3
    (351.9)
    1431
    (1501)
    4145
    (4425)
    5593
    (3817)
    25. Secondary Outcome
    Title 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)
    Description 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.
    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)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) TTMC435 200 mg (Cohort 2, Panel A) TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 25 mg coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 28 days coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 7 9 10 10
    Day 7
    180.9
    (90.04)
    832.3
    (415.1)
    5714
    (4157)
    NA
    (NA)
    NA
    (NA)
    NA
    (NA)
    Day 28
    170.4
    (62.42)
    681.4
    (414.7)
    7117
    (6699)
    186.5
    (115.7)
    986.0
    (1087)
    7182
    (5415)
    26. Secondary Outcome
    Title 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)
    Description 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.
    Time Frame Day 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 8 7 10 3
    Mean (Standard Deviation) [ng/ml]
    820.8
    (580.1)
    2435
    (1909)
    6353
    (5313)
    9613
    (3981)
    27. Secondary Outcome
    Title 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)
    Description 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.
    Time Frame Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 25 mg (Cohort 1, Panel A) TMC435 75 mg (Cohort 1, Panel A) TMC435 200 mg (Cohort 2, Panel A) TMC435 25 mg (Cohort 1, Panel B) TMC435 75 mg (Cohort 1, Panel B) TMC435 200 mg (Cohort 2, Panel B)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22. Treatment-naïve participants received TMC435 25 mg coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 75 mg once daily for 28 days coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-naïve participants received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 10 8 9 8 10
    Day 1
    3035
    (1205)
    12240
    (5663)
    43430
    (22280)
    2853
    (1207)
    12790
    (7888)
    45700
    (24160)
    Day 28
    3961
    (1523)
    16600
    (10680)
    167200
    (154500)
    4527
    (2806)
    23610
    (26780)
    169400
    (126500)
    28. Secondary Outcome
    Title 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)
    Description 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.
    Time Frame Days 1 and 28 (predose and 0.5, 1, 2, 4, 6, 8, and 10 hours postdose)

    Outcome Measure Data

    Analysis Population Description
    All participants who received treatment were included in the pharmacokinetic (PK) analysis, however, due to various reasons (ie, missing samples at certain time points, or exclusion of specific plasma concentrations from the PK analysis) not all PK parameters could always be calculated for each participant.
    Arm/Group Title TMC435 75 mg (Cohort 4, Panel C) TMC435 150 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 4, Panel C) TMC435 200 mg (Cohort 5, Panel D)
    Arm/Group Description Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with ribavirin (RBV) for 28 days + peginterferon alpha-2a (PegIFNα-2a) on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    Measure Participants 9 9 9 4
    Day 1
    11150
    (2903)
    30920
    (13450)
    34410
    (14440)
    51300
    (16720)
    Day 28
    20150
    (14720)
    57440
    (44730)
    152600
    (126600)
    231300
    (96890)

    Adverse Events

    Time Frame Up to 72 weeks.
    Adverse Event Reporting Description
    Arm/Group Title TMC435 25 mg (Cohort 1/Panel A and B) TMC435 75mg (Cohort 1/Panel A and B) Placebo (Cohort 1/Panel A and B) TMC435 200 mg (Cohort 2, Panel A and B) Placebo (Cohort 2/Panel A and B) TMC435 75 mg (Cohort 4/Panel C) TMC435 150 mg (Cohort 4/Panel C) TMC435 200 mg (Cohort 4/Panel C) Placebo (Cohort 4/Panel C) TMC435 200 mg (Cohort 5/Panel D) All TMC435 (All Cohorts)
    Arm/Group Description Treatment-naïve participants received TMC435 25 mg once daily for 7 days followed by TMC435 25 mg once daily coadministered with ribavirin (RBV) for 21 days + peginterferon alpha-2a (PegIFNα-2a) on Days 8, 15, and 22 (Panel A) OR TMC435 25 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received TMC435 75 mg once daily for 7 days followed by TMC435 75 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received placebo (identical in appearance to TMC435 25 mg or 75 mg) once daily for 7 days followed by placebo once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-naïve participants received TMC435 200 mg once daily for 7 days followed by TMC435 200 mg once daily coadministered with RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel 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 RBV for 21 days + PegIFNα-2a on Days 8, 15, and 22 (Panel A) OR placebo once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22 (Panel B) Treatment-experienced non-responders received TMC435 75 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 150 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced non-responders received placebo (identical in appearance to TMC435 75 mg, 150 mg, or 200 mg) once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22. Treatment-experienced relapsers received TMC435 200 mg once daily coadministered with RBV for 28 days + PegIFNα-2a on Days 1, 8, 15, and 22.
    All Cause Mortality
    TMC435 25 mg (Cohort 1/Panel A and B) TMC435 75mg (Cohort 1/Panel A and B) Placebo (Cohort 1/Panel A and B) TMC435 200 mg (Cohort 2, Panel A and B) Placebo (Cohort 2/Panel A and B) TMC435 75 mg (Cohort 4/Panel C) TMC435 150 mg (Cohort 4/Panel C) TMC435 200 mg (Cohort 4/Panel C) Placebo (Cohort 4/Panel C) TMC435 200 mg (Cohort 5/Panel D) All TMC435 (All Cohorts)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    TMC435 25 mg (Cohort 1/Panel A and B) TMC435 75mg (Cohort 1/Panel A and B) Placebo (Cohort 1/Panel A and B) TMC435 200 mg (Cohort 2, Panel A and B) Placebo (Cohort 2/Panel A and B) TMC435 75 mg (Cohort 4/Panel C) TMC435 150 mg (Cohort 4/Panel C) TMC435 200 mg (Cohort 4/Panel C) Placebo (Cohort 4/Panel C) TMC435 200 mg (Cohort 5/Panel D) All TMC435 (All Cohorts)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/18 (11.1%) 3/19 (15.8%) 3/13 (23.1%) 3/18 (16.7%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 2/10 (20%) 0/9 (0%) 1/5 (20%) 13/88 (14.8%)
    Blood and lymphatic system disorders
    Neutropenia 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Thrombocytopenia 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Cardiac disorders
    Sinus arrest 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Ear and labyrinth disorders
    Cupulolithiasis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Endocrine disorders
    Hyperthyroidism 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Infections and infestations
    Bronchitis 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Erysipelas 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Gastroenteritis viral 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Pneumonia 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Pneumonia escherichia 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Sepsis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Sinusitis 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Metabolism and nutrition disorders
    Diabetes mellitus insulin-dependent 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Musculoskeletal and connective tissue disorders
    Exostosis 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Toe deformity 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Breast cancer 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Psychiatric disorders
    Panic attack 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Panic reaction 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Psychotic disorder 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Social circumstances
    Drug abuser 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Social stay hospitalisation 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Other (Not Including Serious) Adverse Events
    TMC435 25 mg (Cohort 1/Panel A and B) TMC435 75mg (Cohort 1/Panel A and B) Placebo (Cohort 1/Panel A and B) TMC435 200 mg (Cohort 2, Panel A and B) Placebo (Cohort 2/Panel A and B) TMC435 75 mg (Cohort 4/Panel C) TMC435 150 mg (Cohort 4/Panel C) TMC435 200 mg (Cohort 4/Panel C) Placebo (Cohort 4/Panel C) TMC435 200 mg (Cohort 5/Panel D) All TMC435 (All Cohorts)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 18/18 (100%) 19/19 (100%) 13/13 (100%) 18/18 (100%) 6/6 (100%) 8/9 (88.9%) 9/9 (100%) 10/10 (100%) 9/9 (100%) 5/5 (100%) 87/88 (98.9%)
    Blood and lymphatic system disorders
    Anaemia 3/18 (16.7%) 2/19 (10.5%) 3/13 (23.1%) 5/18 (27.8%) 1/6 (16.7%) 3/9 (33.3%) 1/9 (11.1%) 2/10 (20%) 0/9 (0%) 0/5 (0%) 16/88 (18.2%)
    Neutropenia 5/18 (27.8%) 7/19 (36.8%) 1/13 (7.7%) 6/18 (33.3%) 2/6 (33.3%) 2/9 (22.2%) 3/9 (33.3%) 3/10 (30%) 1/9 (11.1%) 0/5 (0%) 26/88 (29.5%)
    Thrombocytopenia 4/18 (22.2%) 1/19 (5.3%) 1/13 (7.7%) 1/18 (5.6%) 1/6 (16.7%) 1/9 (11.1%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 8/88 (9.1%)
    Leukopenia 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 4/88 (4.5%)
    Lymphadenopathy 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Pancytopenia 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Cardiac disorders
    Palpitations 2/18 (11.1%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Postural orthostatic tachycardia syndrome 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Sinus arrest 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Tachycardia 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Ear and labyrinth disorders
    Vertigo 4/18 (22.2%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 2/10 (20%) 0/9 (0%) 0/5 (0%) 7/88 (8%)
    Ear discomfort 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hypoacusis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Inner ear inflammation 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Endocrine disorders
    Hyperthyroidism 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hypothyroidism 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Eye disorders
    Abnormal sensation in eye 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Conjunctivitis 2/18 (11.1%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Dry eye 2/18 (11.1%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 2/88 (2.3%)
    Eye oedema 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Eye pain 1/18 (5.6%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Ocular hyperaemia 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Photophobia 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Retinal vein occlusion 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Visual acuity reduced 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Gastrointestinal disorders
    Abdominal pain 1/18 (5.6%) 2/19 (10.5%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 1/5 (20%) 7/88 (8%)
    Abdominal pain upper 1/18 (5.6%) 1/19 (5.3%) 1/13 (7.7%) 2/18 (11.1%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 7/88 (8%)
    Constipation 1/18 (5.6%) 0/19 (0%) 2/13 (15.4%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Diarrhoea 7/18 (38.9%) 4/19 (21.1%) 1/13 (7.7%) 2/18 (11.1%) 0/6 (0%) 3/9 (33.3%) 1/9 (11.1%) 3/10 (30%) 2/9 (22.2%) 1/5 (20%) 21/88 (23.9%)
    Dry mouth 3/18 (16.7%) 4/19 (21.1%) 1/13 (7.7%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 2/5 (40%) 9/88 (10.2%)
    Nausea 9/18 (50%) 6/19 (31.6%) 1/13 (7.7%) 6/18 (33.3%) 2/6 (33.3%) 3/9 (33.3%) 3/9 (33.3%) 4/10 (40%) 1/9 (11.1%) 0/5 (0%) 31/88 (35.2%)
    Toothache 1/18 (5.6%) 1/19 (5.3%) 1/13 (7.7%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Vomiting 3/18 (16.7%) 2/19 (10.5%) 1/13 (7.7%) 2/18 (11.1%) 2/6 (33.3%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 1/5 (20%) 10/88 (11.4%)
    Abdominal distension 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Aphthous stomatitis 1/18 (5.6%) 2/19 (10.5%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Bowel sounds abnormal 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Breath odour 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Cheilitis 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 2/10 (20%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Dyspepsia 0/18 (0%) 2/19 (10.5%) 0/13 (0%) 2/18 (11.1%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 4/88 (4.5%)
    Enteritis 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Eructation 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Flatulence 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 1/5 (20%) 2/88 (2.3%)
    Frequent bowel movements 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Gastric disorder 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Gastric ulcer 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Gastrointestinal disorder 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Gastrointestinal pain 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 1/9 (11.1%) 0/5 (0%) 2/88 (2.3%)
    Gastrooesophageal reflux disease 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Gingival bleeding 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Gingival pain 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Gingivitis 1/18 (5.6%) 1/19 (5.3%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Glossodynia 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Haemorrhoids 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Intestinal functional disorder 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Lip haemorrhage 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Mouth ulceration 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Oesophagitis 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Oral pain 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Periodontitis 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Sensitivity of teeth 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Stomatitis 1/18 (5.6%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    General disorders
    Asthenia 6/18 (33.3%) 9/19 (47.4%) 4/13 (30.8%) 5/18 (27.8%) 1/6 (16.7%) 1/9 (11.1%) 2/9 (22.2%) 3/10 (30%) 2/9 (22.2%) 0/5 (0%) 26/88 (29.5%)
    Chills 2/18 (11.1%) 2/19 (10.5%) 3/13 (23.1%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 2/9 (22.2%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 6/88 (6.8%)
    Fatigue 10/18 (55.6%) 8/19 (42.1%) 5/13 (38.5%) 7/18 (38.9%) 3/6 (50%) 3/9 (33.3%) 5/9 (55.6%) 2/10 (20%) 5/9 (55.6%) 3/5 (60%) 38/88 (43.2%)
    Influenza like illness 6/18 (33.3%) 5/19 (26.3%) 2/13 (15.4%) 4/18 (22.2%) 2/6 (33.3%) 3/9 (33.3%) 1/9 (11.1%) 5/10 (50%) 1/9 (11.1%) 4/5 (80%) 28/88 (31.8%)
    Injection site erythema 1/18 (5.6%) 2/19 (10.5%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 1/9 (11.1%) 1/9 (11.1%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 6/88 (6.8%)
    Injection site reaction 0/18 (0%) 2/19 (10.5%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 5/88 (5.7%)
    Irritability 4/18 (22.2%) 1/19 (5.3%) 1/13 (7.7%) 1/18 (5.6%) 1/6 (16.7%) 1/9 (11.1%) 1/9 (11.1%) 2/10 (20%) 2/9 (22.2%) 2/5 (40%) 12/88 (13.6%)
    Pain 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 3/88 (3.4%)
    Performance status decreased 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 2/9 (22.2%) 0/5 (0%) 0/88 (0%)
    Pyrexia 6/18 (33.3%) 3/19 (15.8%) 2/13 (15.4%) 4/18 (22.2%) 0/6 (0%) 2/9 (22.2%) 3/9 (33.3%) 3/10 (30%) 2/9 (22.2%) 0/5 (0%) 21/88 (23.9%)
    Chest discomfort 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Chest pain 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Face oedema 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Feeling cold 1/18 (5.6%) 2/19 (10.5%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Feeling hot 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Injection site bruising 0/18 (0%) 0/19 (0%) 0/13 (0%) 2/18 (11.1%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Injection site injury 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Malaise 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 2/5 (40%) 3/88 (3.4%)
    Mucosal dryness 2/18 (11.1%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Non-cardiac chest pain 2/18 (11.1%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 4/88 (4.5%)
    Xerosis 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hepatobiliary disorders
    Hepatitis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hyperbilirubinaemia 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Infections and infestations
    Influenza 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 2/9 (22.2%) 0/5 (0%) 1/88 (1.1%)
    Nasopharyngitis 2/18 (11.1%) 2/19 (10.5%) 0/13 (0%) 2/18 (11.1%) 1/6 (16.7%) 1/9 (11.1%) 1/9 (11.1%) 2/10 (20%) 0/9 (0%) 0/5 (0%) 10/88 (11.4%)
    Abscess jaw 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Bronchitis 0/18 (0%) 0/19 (0%) 0/13 (0%) 2/18 (11.1%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 4/88 (4.5%)
    Candidiasis 0/18 (0%) 0/19 (0%) 0/13 (0%) 2/18 (11.1%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Cystitis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Erysipelas 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Eyelid infection 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Furuncle 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Gastroenteritis 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Genital candidiasis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Gingival abscess 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Gingival infection 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Herpes zoster 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Impetigo 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Lower respiratory tract infection 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Oesophageal candidiasis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Oral candidiasis 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Oral fungal infection 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Oral herpes 0/18 (0%) 1/19 (5.3%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 4/88 (4.5%)
    Otitis externa 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Otitis media 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 0/88 (0%)
    Periorbital infection 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Pharyngitis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Rash pustular 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 2/5 (40%) 2/88 (2.3%)
    Respiratory tract infection 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Respiratory tract infection viral 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Rhinitis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Tooth abscess 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Urinary tract infection 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Vulvovaginal mycotic infection 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Injury, poisoning and procedural complications
    Ear injury 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Excoriation 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Eye injury 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Facial bones fracture 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Head injury 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Limb injury 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Periorbital haematoma 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Scratch 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Investigations
    Body temperature increased 0/18 (0%) 0/19 (0%) 2/13 (15.4%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Alanine aminotransferase increased 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 1/5 (20%) 4/88 (4.5%)
    Aspartate aminotransferase increased 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 1/5 (20%) 3/88 (3.4%)
    Blood bilirubin increased 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Blood phosphorus decreased 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Blood uric acid increased 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    ECG signs of myocardial ischaemia 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Haematocrit decreased 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Haemoglobin decreased 1/18 (5.6%) 1/19 (5.3%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Heart rate irregular 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Neutrophil count decreased 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Platelet count decreased 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 1/9 (11.1%) 1/5 (20%) 4/88 (4.5%)
    Weight decreased 1/18 (5.6%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 2/5 (40%) 4/88 (4.5%)
    White blood cell count decreased 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Metabolism and nutrition disorders
    Anorexia 6/18 (33.3%) 1/19 (5.3%) 1/13 (7.7%) 2/18 (11.1%) 0/6 (0%) 0/9 (0%) 3/9 (33.3%) 1/10 (10%) 3/9 (33.3%) 0/5 (0%) 13/88 (14.8%)
    Decreased appetite 2/18 (11.1%) 5/19 (26.3%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 1/9 (11.1%) 1/5 (20%) 9/88 (10.2%)
    Dehydration 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Diabetes mellitus 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hyperglycaemia 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hypertriglyceridaemia 2/18 (11.1%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Hypophosphataemia 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 5/18 (27.8%) 4/19 (21.1%) 1/13 (7.7%) 3/18 (16.7%) 0/6 (0%) 3/9 (33.3%) 4/9 (44.4%) 1/10 (10%) 2/9 (22.2%) 0/5 (0%) 20/88 (22.7%)
    Back pain 0/18 (0%) 1/19 (5.3%) 3/13 (23.1%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 2/10 (20%) 3/9 (33.3%) 2/5 (40%) 6/88 (6.8%)
    Bone pain 1/18 (5.6%) 2/19 (10.5%) 0/13 (0%) 2/18 (11.1%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 5/88 (5.7%)
    Myalgia 4/18 (22.2%) 4/19 (21.1%) 4/13 (30.8%) 4/18 (22.2%) 1/6 (16.7%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 3/9 (33.3%) 1/5 (20%) 15/88 (17%)
    Pain in extremity 2/18 (11.1%) 1/19 (5.3%) 2/13 (15.4%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Flank pain 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Groin pain 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Joint ankylosis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Joint swelling 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Muscle spasms 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Muscle tightness 2/18 (11.1%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Neck pain 1/18 (5.6%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Osteoarthritis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Spinal osteoarthritis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Nervous system disorders
    Disturbance in attention 2/18 (11.1%) 1/19 (5.3%) 1/13 (7.7%) 1/18 (5.6%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 1/10 (10%) 1/9 (11.1%) 2/5 (40%) 9/88 (10.2%)
    Dizziness 3/18 (16.7%) 1/19 (5.3%) 2/13 (15.4%) 1/18 (5.6%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 4/5 (80%) 10/88 (11.4%)
    Dysgeusia 1/18 (5.6%) 1/19 (5.3%) 3/13 (23.1%) 1/18 (5.6%) 0/6 (0%) 2/9 (22.2%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 6/88 (6.8%)
    Headache 13/18 (72.2%) 11/19 (57.9%) 6/13 (46.2%) 3/18 (16.7%) 4/6 (66.7%) 5/9 (55.6%) 7/9 (77.8%) 3/10 (30%) 6/9 (66.7%) 4/5 (80%) 46/88 (52.3%)
    Amnesia 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 2/5 (40%) 2/88 (2.3%)
    Hypoaesthesia 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Intercostal neuralgia 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Lethargy 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Memory impairment 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Migraine 1/18 (5.6%) 1/19 (5.3%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Migraine with aura 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Paraesthesia 0/18 (0%) 2/19 (10.5%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Restless legs syndrome 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Sciatica 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Somnolence 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Syncope 1/18 (5.6%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Psychiatric disorders
    Depression 6/18 (33.3%) 3/19 (15.8%) 0/13 (0%) 4/18 (22.2%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 1/9 (11.1%) 0/5 (0%) 14/88 (15.9%)
    Insomnia 3/18 (16.7%) 2/19 (10.5%) 3/13 (23.1%) 4/18 (22.2%) 1/6 (16.7%) 0/9 (0%) 2/9 (22.2%) 1/10 (10%) 3/9 (33.3%) 0/5 (0%) 12/88 (13.6%)
    Loss of libido 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 2/9 (22.2%) 0/5 (0%) 0/88 (0%)
    Mood altered 1/18 (5.6%) 1/19 (5.3%) 1/13 (7.7%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Nervousness 3/18 (16.7%) 1/19 (5.3%) 2/13 (15.4%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 2/9 (22.2%) 0/5 (0%) 4/88 (4.5%)
    Sleep disorder 4/18 (22.2%) 1/19 (5.3%) 1/13 (7.7%) 2/18 (11.1%) 0/6 (0%) 0/9 (0%) 2/9 (22.2%) 1/10 (10%) 1/9 (11.1%) 0/5 (0%) 10/88 (11.4%)
    Affective disorder 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Aggression 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 1/88 (1.1%)
    Agitation 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 2/88 (2.3%)
    Alcoholism 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Anxiety 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Dependence 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Depressed mood 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 2/10 (20%) 1/9 (11.1%) 0/5 (0%) 4/88 (4.5%)
    Depressive symptom 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Emotional disorder 1/18 (5.6%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Impulsive behaviour 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Libido decreased 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Listless 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Neurosis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 0/88 (0%)
    Tearfulness 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Renal and urinary disorders
    Dysuria 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Nephrolithiasis 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Pollakiuria 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 2/88 (2.3%)
    Polyuria 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Reproductive system and breast disorders
    Epididymitis 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Erectile dysfunction 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 1/9 (11.1%) 0/5 (0%) 1/88 (1.1%)
    Respiratory, thoracic and mediastinal disorders
    Cough 5/18 (27.8%) 7/19 (36.8%) 4/13 (30.8%) 1/18 (5.6%) 3/6 (50%) 2/9 (22.2%) 3/9 (33.3%) 1/10 (10%) 3/9 (33.3%) 0/5 (0%) 19/88 (21.6%)
    Dyspnoea 5/18 (27.8%) 4/19 (21.1%) 3/13 (23.1%) 1/18 (5.6%) 1/6 (16.7%) 2/9 (22.2%) 2/9 (22.2%) 4/10 (40%) 0/9 (0%) 0/5 (0%) 18/88 (20.5%)
    Dyspnoea exertional 1/18 (5.6%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 1/6 (16.7%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 3/88 (3.4%)
    Epistaxis 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 1/9 (11.1%) 0/10 (0%) 1/9 (11.1%) 3/5 (60%) 6/88 (6.8%)
    Pharyngolaryngeal pain 1/18 (5.6%) 2/19 (10.5%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 1/10 (10%) 1/9 (11.1%) 0/5 (0%) 5/88 (5.7%)
    Hiccups 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Lung disorder 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Nasal congestion 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Nasal dryness 0/18 (0%) 2/19 (10.5%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Rhinorrhoea 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Rhonchi 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Sneezing 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 1/9 (11.1%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Throat irritation 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Wheezing 1/18 (5.6%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Skin and subcutaneous tissue disorders
    Alopecia 3/18 (16.7%) 6/19 (31.6%) 2/13 (15.4%) 2/18 (11.1%) 0/6 (0%) 2/9 (22.2%) 3/9 (33.3%) 1/10 (10%) 1/9 (11.1%) 0/5 (0%) 17/88 (19.3%)
    Dry skin 5/18 (27.8%) 9/19 (47.4%) 2/13 (15.4%) 3/18 (16.7%) 1/6 (16.7%) 0/9 (0%) 2/9 (22.2%) 0/10 (0%) 2/9 (22.2%) 1/5 (20%) 20/88 (22.7%)
    Eczema 1/18 (5.6%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 2/9 (22.2%) 2/9 (22.2%) 1/10 (10%) 2/9 (22.2%) 0/5 (0%) 7/88 (8%)
    Night sweats 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 2/6 (33.3%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Pruritus 1/18 (5.6%) 3/19 (15.8%) 2/13 (15.4%) 5/18 (27.8%) 0/6 (0%) 3/9 (33.3%) 3/9 (33.3%) 3/10 (30%) 5/9 (55.6%) 3/5 (60%) 21/88 (23.9%)
    Pruritus generalised 5/18 (27.8%) 1/19 (5.3%) 2/13 (15.4%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 1/9 (11.1%) 2/10 (20%) 0/9 (0%) 1/5 (20%) 10/88 (11.4%)
    Rash 1/18 (5.6%) 3/19 (15.8%) 3/13 (23.1%) 4/18 (22.2%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 1/9 (11.1%) 2/5 (40%) 11/88 (12.5%)
    Urticaria localised 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Cold sweat 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Dermatitis 2/18 (11.1%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Dermatitis allergic 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Dermatitis atopic 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Erythema 0/18 (0%) 0/19 (0%) 0/13 (0%) 2/18 (11.1%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Hyperhidrosis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hypoaesthesia facial 0/18 (0%) 0/19 (0%) 1/13 (7.7%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Lichen planus 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Nail discolouration 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Photosensitivity reaction 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Purpura 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Rash erythematous 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Rash generalised 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Rash macular 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 1/88 (1.1%)
    Seborrhoeic dermatitis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Skin burning sensation 0/18 (0%) 0/19 (0%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 1/5 (20%) 3/88 (3.4%)
    Skin fissures 1/18 (5.6%) 1/19 (5.3%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Skin irritation 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Vascular disorders
    Deep vein thrombosis 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Flushing 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 1/6 (16.7%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 0/88 (0%)
    Hot flush 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Hypertension 0/18 (0%) 1/19 (5.3%) 0/13 (0%) 1/18 (5.6%) 0/6 (0%) 0/9 (0%) 1/9 (11.1%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 3/88 (3.4%)
    Hypotension 0/18 (0%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Phlebitis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 1/10 (10%) 0/9 (0%) 0/5 (0%) 2/88 (2.3%)
    Raynaud's phenomenon 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)
    Vasculitis 1/18 (5.6%) 0/19 (0%) 0/13 (0%) 0/18 (0%) 0/6 (0%) 0/9 (0%) 0/9 (0%) 0/10 (0%) 0/9 (0%) 0/5 (0%) 1/88 (1.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Global Clinical Development Manager
    Organization Jan-Cil France
    Phone
    Email ClinicalTrialDisclosure@its.jnj.com
    Responsible Party:
    Tibotec Pharmaceuticals, Ireland
    ClinicalTrials.gov Identifier:
    NCT00561353
    Other Study ID Numbers:
    • CR012607
    • TMC435350-TiDP16-C201
    • NCT00614185
    First Posted:
    Nov 20, 2007
    Last Update Posted:
    May 20, 2014
    Last Verified:
    May 1, 2014