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Trial record 98 of 546 for:    "Viral Infectious Disease" | "Peginterferon alfa-2a"

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

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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Hepatitis C, Chronic
Interventions Drug: TMC435
Drug: Placebo
Drug: Peginterferon (PegIFNα-2a)
Drug: Ribavirin
Enrollment 121
Recruitment Details The study was conducted at 25 sites in 6 countries: Belgium, France, Germany, Poland, the Netherlands, and the United Kingdom.
Pre-assignment Details 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)
Hide 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
Reason Not Completed
Subject reached a virologic endpoint             2             1             1             4             1             3             4             4             5             0
Subject ineligible to continue the trial             0             0             0             0             0             1             1             0             2             1
Not specified             1             0             1             0             0             2             0             0             0             0
Adverse Event             0             0             0             2             0             0             1             0             0             1
Lost to Follow-up             2             0             1             0             0             0             0             0             0             0
Withdrawal by Subject             0             2             0             0             0             0             0             0             0             0
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
Hide 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 Number of Baseline Participants 18 19 13 18 6 9 9 10 9 5 116
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 18 participants 19 participants 13 participants 18 participants 6 participants 9 participants 9 participants 10 participants 9 participants 5 participants 116 participants
52
(22 to 64)
47
(22 to 70)
45
(19 to 60)
46.5
(19 to 68)
44.5
(19 to 50)
53
(38 to 62)
56
(32 to 67)
55.5
(28 to 69)
47
(21 to 57)
56
(33 to 66)
49
(19 to 70)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 19 participants 13 participants 18 participants 6 participants 9 participants 9 participants 10 participants 9 participants 5 participants 116 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%
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
  80.0%
9
 100.0%
5
 100.0%
85
  73.3%
The Number of Participants Randomized to each Treatment Panel   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 18 participants 19 participants 13 participants 18 participants 6 participants 9 participants 9 participants 10 participants 9 participants 5 participants 116 participants
Panel A 9 10 6 9 3 0 0 0 0 0 37
Panel B 9 9 7 9 3 0 0 0 0 0 37
Panel C 0 0 0 0 0 9 9 10 9 0 37
Panel D 0 0 0 0 0 0 0 0 0 5 5
[1]
Measure Description: The table below shows the number of participants in Cohorts 1, 2, 4 and 5 that were randomized to treatment Panels A, B, C, and D.
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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 10 6 9 3
Mean (Standard Error)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 7 9 3
Mean (Standard Error)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 4
Mean (Standard Error)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 10 6 9 3
Mean (Standard Error)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 7 9 3
Mean (Standard Error)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 5
Mean (Standard Error)
Unit of Measure: 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 10 6 9 3
Measure Type: Number
Unit of Measure: Participants
Day 2/3: > or = 2 log10 change from baseline 6 9 0 9 0
Day 7: > or = 2 log10 change from baseline 7 9 0 9 0
Day 28: > or = 2 log10 change from baseline 7 9 4 8 1
Day 2/3: <25 IU/mL detectable or undetectable 1 1 0 1 0
Day 7: <25 IU/mL detectable or undetectable 1 0 0 1 0
Day 28: <25 IU/mL detectable or undetectable 5 8 1 7 0
Day 2/3: <25 IU/mL undetectable 0 0 0 0 0
Day 7: <25 IU/mL undetectable 0 0 0 0 0
Day 28: <25 IU/mL undetectable 5 5 1 7 0
Day 2/3: <100 IU/mL 1 1 0 1 0
Day 7: <100 IU/mL 1 3 0 4 0
Day 28: <100 IU/mL 6 8 1 7 0
Day 2/3: <1000 IU/mL 2 5 0 6 0
Day 7: <1000 IU/mL 3 6 0 7 0
Day 28: <1000 IU/mL 7 8 2 7 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 7 9 3
Measure Type: Number
Unit of Measure: Participants
Day 2/3: > or = 2 log10 change from baseline 7 9 2 9 2
Day 7: > or = 2 log10 change from baseline 7 9 2 9 1
Day 28: > or = 2 log10 change from baseline 8 9 6 9 2
Day 2/3: <25 IU/mL detectable or undetectable 0 0 0 0 0
Day 7: <25 IU/mL detectable or undetectable 1 1 0 3 0
Day 28: <25 IU/mL detectable or undetectable 6 9 3 9 1
Day 2/3: <25 IU/mL undetectable 0 0 0 0 0
Day 7: <25 IU/mL undetectable 0 0 0 1 0
Day 28: <25 IU/mL undetectable 3 8 2 6 0
Day 2/3: <100 IU/mL 0 1 0 1 0
Day 7: <100 IU/mL 1 6 0 5 0
Day 28: <100 IU/mL 6 9 3 9 1
Day 2/3: <1000 IU/mL 4 5 0 6 0
Day 7: <1000 IU/mL 5 9 0 9 0
Day 28: <1000 IU/mL 7 9 4 9 2
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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 5
Measure Type: Number
Unit of Measure: Participants
Day 2/3: > or = 2 log10 change from baseline 8 9 10 1 4
Day 7: > or = 2 log10 change from baseline 8 9 10 0 5
Day 28: > or = 2 log10 change from baseline 8 9 10 2 4
Day 2/3: <25 IU/mL detectable or undetectable 0 0 0 0 0
Day 7: <25 IU/mL detectable or undetectable 0 2 3 0 0
Day 28: <25 IU/mL detectable or undetectable 4 7 7 0 4
Day 2/3: <25 IU/mL undetectable 0 0 0 0 0
Day 7: <25 IU/mL undetectable 0 0 0 0 0
Day 28: <25 IU/mL undetectable 2 5 3 0 3
Day 2/3: <100 IU/mL 0 0 0 0 0
Day 7: <100 IU/mL 2 4 5 0 0
Day 28: <100 IU/mL 6 8 7 0 4
Day 2/3: <1000 IU/mL 3 3 5 0 0
Day 7: <1000 IU/mL 5 7 8 0 3
Day 28: <1000 IU/mL 6 8 10 0 4
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 18 19 13 18 6
Measure Type: Number
Unit of Measure: Participants
RVR 8 13 3 13 0
EVR 16 19 12 16 6
cEVR 13 17 7 16 5
eRVR 8 13 3 13 0
Partial response 0 0 0 0 1
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 5
Measure Type: Number
Unit of Measure: Participants
RVR 2 5 3 0 3
EVR 6 7 8 8 4
cEVR 4 4 5 0 3
eRVR 2 4 3 0 3
Partial response 0 1 1 5 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 10 6 9 3
Measure Type: Number
Unit of Measure: Participants
3 1 6 0 3
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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 7 9 3
Measure Type: Number
Unit of Measure: Participants
2 0 5 0 1
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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 5
Measure Type: Number
Unit of Measure: Participants
1 0 0 8 1
15.Secondary Outcome
Title Viral Breakthrough in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1, Panel A and B)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 18 19 13 18 6
Measure Type: Number
Unit of Measure: Participants
Entire treatment period (48 Wks) 3 3 0 4 0
During TMC435/Placebo treatment (4 Wks) 2 2 0 1 0
During treatment with RBV and PegIFNα-2a (44 Wks) 1 1 0 3 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)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 5
Measure Type: Number
Unit of Measure: Participants
Entire treatment period (48 Wks) 3 4 4 1 1
During TMC435/Placebo treatment (4 Wks) 2 1 0 1 0
During treatment with RBV and PegIFNα-2a (44 Wks) 1 3 4 0 1
17.Secondary Outcome
Title Viral Relapse in Treatment-Naïve Hepatitis C Virus (HCV)-Infected Participants (Cohort 1 and 2, Panel A and B Combined)
Hide 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
Hide Outcome Measure Data
Hide 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)
Hide 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).
Overall Number of Participants Analyzed 15 18 12 14 5
Measure Type: Number
Unit of Measure: Participants
Relapse 2 1 2 1 0
No relapse 12 17 10 13 5
Missing follow-up 1 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)
Hide 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
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Hide 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)
Hide 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.
Overall Number of Participants Analyzed 6 3 6 3 3
Measure Type: Number
Unit of Measure: Participants
Relapse 3 0 1 3 0
No relapse 3 3 5 0 3
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)
Hide 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)
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Hide 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)
Hide 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).
Overall Number of Participants Analyzed 18 19 13 18 6
Measure Type: Number
Unit of Measure: Participants
SVR4 12 16 11 12 5
SVR8 12 14 9 12 5
SVR12 12 15 9 12 5
SVR24 10 15 9 12 5
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)
Hide 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)
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Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 10 9 5
Measure Type: Number
Unit of Measure: Participants
SVR4 2 3 4 1 3
SVR8 1 3 4 0 3
SVR12 1 3 5 0 3
SVR24 1 3 5 0 3
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)
Hide 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)
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Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 10 8 9 8 10
Mean (Standard Deviation)
Unit of Measure: ng/mL
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 9 4
Mean (Standard Deviation)
Unit of Measure: ng/mL
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)
Hide 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)
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Hide 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)
Hide 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.
Overall Number of Participants Analyzed 8 9 8 9 9 10
Mean (Standard Deviation)
Unit of Measure: ng/ml
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 8 10 5
Mean (Standard Deviation)
Unit of Measure: ng/mL
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 7 9 10 10
Mean (Standard Deviation)
Unit of Measure: ng/ml
Day 7 180.9  (90.04) 832.3  (415.1) 5714  (4157) NA [1]   (NA) NA [1]   (NA) NA [1]   (NA)
Day 28 170.4  (62.42) 681.4  (414.7) 7117  (6699) 186.5  (115.7) 986.0  (1087) 7182  (5415)
[1]
Value not measured
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 8 7 10 3
Mean (Standard Deviation)
Unit of Measure: 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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 10 8 9 8 10
Mean (Standard Deviation)
Unit of Measure: ng.h/mL
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)
Hide 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)
Hide Outcome Measure Data
Hide 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)
Hide 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.
Overall Number of Participants Analyzed 9 9 9 4
Mean (Standard Deviation)
Unit of Measure: ng.h/mL
Day 1 11150  (2903) 30920  (13450) 34410  (14440) 51300  (16720)
Day 28 20150  (14720) 57440  (44730) 152600  (126600) 231300  (96890)
Time Frame Up to 72 weeks.
Adverse Event Reporting Description [Not Specified]
 
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)
Hide 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. [Not Specified]
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/18 (11.11%)   3/19 (15.79%)   3/13 (23.08%)   3/18 (16.67%)   0/6 (0.00%)   1/9 (11.11%)   1/9 (11.11%)   2/10 (20.00%)   0/9 (0.00%)   1/5 (20.00%)   13/88 (14.77%) 
Blood and lymphatic system disorders                       
Neutropenia * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Thrombocytopenia * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Cardiac disorders                       
Sinus arrest * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Ear and labyrinth disorders                       
Cupulolithiasis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Endocrine disorders                       
Hyperthyroidism * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Infections and infestations                       
Bronchitis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Erysipelas * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Gastroenteritis viral * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Pneumonia * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Pneumonia escherichia * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Sepsis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Sinusitis * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Metabolism and nutrition disorders                       
Diabetes mellitus insulin-dependent * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Musculoskeletal and connective tissue disorders                       
Exostosis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Toe deformity * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                       
Bowen's disease * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Breast cancer * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Psychiatric disorders                       
Panic attack * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Panic reaction * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Psychotic disorder * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Social circumstances                       
Drug abuser * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Social stay hospitalisation * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA Version 10.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
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 (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   18/18 (100.00%)   19/19 (100.00%)   13/13 (100.00%)   18/18 (100.00%)   6/6 (100.00%)   8/9 (88.89%)   9/9 (100.00%)   10/10 (100.00%)   9/9 (100.00%)   5/5 (100.00%)   87/88 (98.86%) 
Blood and lymphatic system disorders                       
Anaemia * 1  3/18 (16.67%)  2/19 (10.53%)  3/13 (23.08%)  5/18 (27.78%)  1/6 (16.67%)  3/9 (33.33%)  1/9 (11.11%)  2/10 (20.00%)  0/9 (0.00%)  0/5 (0.00%)  16/88 (18.18%) 
Neutropenia * 1  5/18 (27.78%)  7/19 (36.84%)  1/13 (7.69%)  6/18 (33.33%)  2/6 (33.33%)  2/9 (22.22%)  3/9 (33.33%)  3/10 (30.00%)  1/9 (11.11%)  0/5 (0.00%)  26/88 (29.55%) 
Thrombocytopenia * 1  4/18 (22.22%)  1/19 (5.26%)  1/13 (7.69%)  1/18 (5.56%)  1/6 (16.67%)  1/9 (11.11%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  8/88 (9.09%) 
Leukopenia * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  1/9 (11.11%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  4/88 (4.55%) 
Lymphadenopathy * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Pancytopenia * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Cardiac disorders                       
Palpitations * 1  2/18 (11.11%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Postural orthostatic tachycardia syndrome * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Sinus arrest * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Tachycardia * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Ear and labyrinth disorders                       
Vertigo * 1  4/18 (22.22%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  2/10 (20.00%)  0/9 (0.00%)  0/5 (0.00%)  7/88 (7.95%) 
Ear discomfort * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Hypoacusis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Inner ear inflammation * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Endocrine disorders                       
Hyperthyroidism * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Hypothyroidism * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Eye disorders                       
Abnormal sensation in eye * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Conjunctivitis * 1  2/18 (11.11%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Dry eye * 1  2/18 (11.11%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/5 (0.00%)  2/88 (2.27%) 
Eye oedema * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Eye pain * 1  1/18 (5.56%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Ocular hyperaemia * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Photophobia * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Retinal vein occlusion * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Visual acuity reduced * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Gastrointestinal disorders                       
Abdominal pain * 1  1/18 (5.56%)  2/19 (10.53%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  1/5 (20.00%)  7/88 (7.95%) 
Abdominal pain upper * 1  1/18 (5.56%)  1/19 (5.26%)  1/13 (7.69%)  2/18 (11.11%)  0/6 (0.00%)  1/9 (11.11%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  7/88 (7.95%) 
Constipation * 1  1/18 (5.56%)  0/19 (0.00%)  2/13 (15.38%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Diarrhoea * 1  7/18 (38.89%)  4/19 (21.05%)  1/13 (7.69%)  2/18 (11.11%)  0/6 (0.00%)  3/9 (33.33%)  1/9 (11.11%)  3/10 (30.00%)  2/9 (22.22%)  1/5 (20.00%)  21/88 (23.86%) 
Dry mouth * 1  3/18 (16.67%)  4/19 (21.05%)  1/13 (7.69%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  2/5 (40.00%)  9/88 (10.23%) 
Nausea * 1  9/18 (50.00%)  6/19 (31.58%)  1/13 (7.69%)  6/18 (33.33%)  2/6 (33.33%)  3/9 (33.33%)  3/9 (33.33%)  4/10 (40.00%)  1/9 (11.11%)  0/5 (0.00%)  31/88 (35.23%) 
Toothache * 1  1/18 (5.56%)  1/19 (5.26%)  1/13 (7.69%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Vomiting * 1  3/18 (16.67%)  2/19 (10.53%)  1/13 (7.69%)  2/18 (11.11%)  2/6 (33.33%)  1/9 (11.11%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  1/5 (20.00%)  10/88 (11.36%) 
Abdominal distension * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Aphthous stomatitis * 1  1/18 (5.56%)  2/19 (10.53%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Bowel sounds abnormal * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Breath odour * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Cheilitis * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  2/10 (20.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Dyspepsia * 1  0/18 (0.00%)  2/19 (10.53%)  0/13 (0.00%)  2/18 (11.11%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/5 (0.00%)  4/88 (4.55%) 
Enteritis * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Eructation * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Flatulence * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  1/5 (20.00%)  2/88 (2.27%) 
Frequent bowel movements * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Gastric disorder * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Gastric ulcer * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Gastrointestinal disorder * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Gastrointestinal pain * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  1/9 (11.11%)  0/5 (0.00%)  2/88 (2.27%) 
Gastrooesophageal reflux disease * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Gingival bleeding * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Gingival pain * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Gingivitis * 1  1/18 (5.56%)  1/19 (5.26%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Glossodynia * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Haemorrhoids * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Intestinal functional disorder * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Lip haemorrhage * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Mouth ulceration * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Oesophagitis * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Oral pain * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Periodontitis * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Sensitivity of teeth * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Stomatitis * 1  1/18 (5.56%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
General disorders                       
Asthenia * 1  6/18 (33.33%)  9/19 (47.37%)  4/13 (30.77%)  5/18 (27.78%)  1/6 (16.67%)  1/9 (11.11%)  2/9 (22.22%)  3/10 (30.00%)  2/9 (22.22%)  0/5 (0.00%)  26/88 (29.55%) 
Chills * 1  2/18 (11.11%)  2/19 (10.53%)  3/13 (23.08%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  2/9 (22.22%)  0/10 (0.00%)  1/9 (11.11%)  0/5 (0.00%)  6/88 (6.82%) 
Fatigue * 1  10/18 (55.56%)  8/19 (42.11%)  5/13 (38.46%)  7/18 (38.89%)  3/6 (50.00%)  3/9 (33.33%)  5/9 (55.56%)  2/10 (20.00%)  5/9 (55.56%)  3/5 (60.00%)  38/88 (43.18%) 
Influenza like illness * 1  6/18 (33.33%)  5/19 (26.32%)  2/13 (15.38%)  4/18 (22.22%)  2/6 (33.33%)  3/9 (33.33%)  1/9 (11.11%)  5/10 (50.00%)  1/9 (11.11%)  4/5 (80.00%)  28/88 (31.82%) 
Injection site erythema * 1  1/18 (5.56%)  2/19 (10.53%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  1/9 (11.11%)  1/9 (11.11%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  6/88 (6.82%) 
Injection site reaction * 1  0/18 (0.00%)  2/19 (10.53%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  5/88 (5.68%) 
Irritability * 1  4/18 (22.22%)  1/19 (5.26%)  1/13 (7.69%)  1/18 (5.56%)  1/6 (16.67%)  1/9 (11.11%)  1/9 (11.11%)  2/10 (20.00%)  2/9 (22.22%)  2/5 (40.00%)  12/88 (13.64%) 
Pain * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  1/6 (16.67%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  1/9 (11.11%)  0/5 (0.00%)  3/88 (3.41%) 
Performance status decreased * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  2/9 (22.22%)  0/5 (0.00%)  0/88 (0.00%) 
Pyrexia * 1  6/18 (33.33%)  3/19 (15.79%)  2/13 (15.38%)  4/18 (22.22%)  0/6 (0.00%)  2/9 (22.22%)  3/9 (33.33%)  3/10 (30.00%)  2/9 (22.22%)  0/5 (0.00%)  21/88 (23.86%) 
Chest discomfort * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Chest pain * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Face oedema * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Feeling cold * 1  1/18 (5.56%)  2/19 (10.53%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Feeling hot * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Injection site bruising * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  2/18 (11.11%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Injection site injury * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Malaise * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  2/5 (40.00%)  3/88 (3.41%) 
Mucosal dryness * 1  2/18 (11.11%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Non-cardiac chest pain * 1  2/18 (11.11%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  4/88 (4.55%) 
Xerosis * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Hepatobiliary disorders                       
Hepatitis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Hyperbilirubinaemia * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Infections and infestations                       
Influenza * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  2/9 (22.22%)  0/5 (0.00%)  1/88 (1.14%) 
Nasopharyngitis * 1  2/18 (11.11%)  2/19 (10.53%)  0/13 (0.00%)  2/18 (11.11%)  1/6 (16.67%)  1/9 (11.11%)  1/9 (11.11%)  2/10 (20.00%)  0/9 (0.00%)  0/5 (0.00%)  10/88 (11.36%) 
Abscess jaw * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Bronchitis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  2/18 (11.11%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  4/88 (4.55%) 
Candidiasis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  2/18 (11.11%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Cystitis * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Erysipelas * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Eyelid infection * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Furuncle * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Gastroenteritis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Genital candidiasis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Gingival abscess * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Gingival infection * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Herpes zoster * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Impetigo * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Lower respiratory tract infection * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Oesophageal candidiasis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Oral candidiasis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Oral fungal infection * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Oral herpes * 1  0/18 (0.00%)  1/19 (5.26%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  4/88 (4.55%) 
Otitis externa * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Otitis media * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  1/9 (11.11%)  0/5 (0.00%)  0/88 (0.00%) 
Periorbital infection * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Pharyngitis * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Rash pustular * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  2/5 (40.00%)  2/88 (2.27%) 
Respiratory tract infection * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Respiratory tract infection viral * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Rhinitis * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Tooth abscess * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Urinary tract infection * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Vulvovaginal mycotic infection * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Injury, poisoning and procedural complications                       
Ear injury * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Excoriation * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Eye injury * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Facial bones fracture * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Head injury * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Limb injury * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Periorbital haematoma * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Scratch * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Investigations                       
Body temperature increased * 1  0/18 (0.00%)  0/19 (0.00%)  2/13 (15.38%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Alanine aminotransferase increased * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  1/5 (20.00%)  4/88 (4.55%) 
Aspartate aminotransferase increased * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  1/5 (20.00%)  3/88 (3.41%) 
Blood bilirubin increased * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Blood phosphorus decreased * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Blood uric acid increased * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
ECG signs of myocardial ischaemia * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Haematocrit decreased * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Haemoglobin decreased * 1  1/18 (5.56%)  1/19 (5.26%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Heart rate irregular * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Neutrophil count decreased * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Platelet count decreased * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  1/9 (11.11%)  1/5 (20.00%)  4/88 (4.55%) 
Weight decreased * 1  1/18 (5.56%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  2/5 (40.00%)  4/88 (4.55%) 
White blood cell count decreased * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Metabolism and nutrition disorders                       
Anorexia * 1  6/18 (33.33%)  1/19 (5.26%)  1/13 (7.69%)  2/18 (11.11%)  0/6 (0.00%)  0/9 (0.00%)  3/9 (33.33%)  1/10 (10.00%)  3/9 (33.33%)  0/5 (0.00%)  13/88 (14.77%) 
Decreased appetite * 1  2/18 (11.11%)  5/19 (26.32%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  1/9 (11.11%)  1/5 (20.00%)  9/88 (10.23%) 
Dehydration * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Diabetes mellitus * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Hyperglycaemia * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Hypertriglyceridaemia * 1  2/18 (11.11%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Hypophosphataemia * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Musculoskeletal and connective tissue disorders                       
Arthralgia * 1  5/18 (27.78%)  4/19 (21.05%)  1/13 (7.69%)  3/18 (16.67%)  0/6 (0.00%)  3/9 (33.33%)  4/9 (44.44%)  1/10 (10.00%)  2/9 (22.22%)  0/5 (0.00%)  20/88 (22.73%) 
Back pain * 1  0/18 (0.00%)  1/19 (5.26%)  3/13 (23.08%)  1/18 (5.56%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  2/10 (20.00%)  3/9 (33.33%)  2/5 (40.00%)  6/88 (6.82%) 
Bone pain * 1  1/18 (5.56%)  2/19 (10.53%)  0/13 (0.00%)  2/18 (11.11%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  5/88 (5.68%) 
Myalgia * 1  4/18 (22.22%)  4/19 (21.05%)  4/13 (30.77%)  4/18 (22.22%)  1/6 (16.67%)  1/9 (11.11%)  0/9 (0.00%)  1/10 (10.00%)  3/9 (33.33%)  1/5 (20.00%)  15/88 (17.05%) 
Pain in extremity * 1  2/18 (11.11%)  1/19 (5.26%)  2/13 (15.38%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  3/88 (3.41%) 
Flank pain * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Groin pain * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Joint ankylosis * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Joint swelling * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Muscle spasms * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Muscle tightness * 1  2/18 (11.11%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Neck pain * 1  1/18 (5.56%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Osteoarthritis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Spinal osteoarthritis * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Nervous system disorders                       
Disturbance in attention * 1  2/18 (11.11%)  1/19 (5.26%)  1/13 (7.69%)  1/18 (5.56%)  0/6 (0.00%)  1/9 (11.11%)  1/9 (11.11%)  1/10 (10.00%)  1/9 (11.11%)  2/5 (40.00%)  9/88 (10.23%) 
Dizziness * 1  3/18 (16.67%)  1/19 (5.26%)  2/13 (15.38%)  1/18 (5.56%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  4/5 (80.00%)  10/88 (11.36%) 
Dysgeusia * 1  1/18 (5.56%)  1/19 (5.26%)  3/13 (23.08%)  1/18 (5.56%)  0/6 (0.00%)  2/9 (22.22%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  6/88 (6.82%) 
Headache * 1  13/18 (72.22%)  11/19 (57.89%)  6/13 (46.15%)  3/18 (16.67%)  4/6 (66.67%)  5/9 (55.56%)  7/9 (77.78%)  3/10 (30.00%)  6/9 (66.67%)  4/5 (80.00%)  46/88 (52.27%) 
Amnesia * 1  0/18 (0.00%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  2/5 (40.00%)  2/88 (2.27%) 
Hypoaesthesia * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Intercostal neuralgia * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Lethargy * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  1/6 (16.67%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  0/88 (0.00%) 
Memory impairment * 1  0/18 (0.00%)  1/19 (5.26%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Migraine * 1  1/18 (5.56%)  1/19 (5.26%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Migraine with aura * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  1/10 (10.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Paraesthesia * 1  0/18 (0.00%)  2/19 (10.53%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Restless legs syndrome * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  1/5 (20.00%)  1/88 (1.14%) 
Sciatica * 1  1/18 (5.56%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Somnolence * 1  0/18 (0.00%)  0/19 (0.00%)  0/13 (0.00%)  0/18 (0.00%)  0/6 (0.00%)  1/9 (11.11%)  1/9 (11.11%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  2/88 (2.27%) 
Syncope * 1  1/18 (5.56%)  0/19 (0.00%)  1/13 (7.69%)  0/18 (0.00%)  0/6 (0.00%)  0/9 (0.00%)  0/9 (0.00%)  0/10 (0.00%)  0/9 (0.00%)  0/5 (0.00%)  1/88 (1.14%) 
Psychiatric disorders