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    Clinical Trial Results:
    A Phase 3, Open-Label Study to Evaluate the Safety and Efficacy of TMC435 plus Pegylated Interferon alfa-2a and Ribavirin Administered for 12 Weeks in Treatment-Naïve Subjects with Chronic Genotype 1 or Genotype 4 HCV Infection

    Summary
    EudraCT number
    2012-004905-29
    Trial protocol
    BE   GB   AT   IT   ES   DE  
    Global end of trial date
    31 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Sep 2016
    First version publication date
    08 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC435HPC3014
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01846832
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Cilag International NV
    Sponsor organisation address
    Antwerpseweg 15-17, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to determine the efficacy of simeprevir (SMV) plus pegylated interferon alpha-2a(PegIFNα-2a) and ribavirin (RBV) when administered for 12 weeks in treatment-naïve subjects with chronic genotype 1 hepatitis C virus (HCV) infection, as measured by the proportion of subjects with sustained virologic response 12 (SVR12) and to assess the safety and tolerability of SMV plus PegIFNα-2a and RBV when administered for 12 weeks in treatment-naïve subjects with chronic genotype 1 HCV infection.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations were based upon the type, incidence, and severity of AEs reported throughout the study, changes in clinical laboratory tests (hematology, biochemistry and urinalysis), vital sign measurements, 12-lead electrocardiograms (ECGs) and physical examination (including weight, height, and temperature).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 43
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Austria: 30
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    France: 50
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Saudi Arabia: 17
    Worldwide total number of subjects
    230
    EEA total number of subjects
    213
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    226
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 31 sites in 8 countries.

    Pre-assignment
    Screening details
    In total, 277 subjects were screened, of whom 230 were enrolled and treated. Two subjects were enrolled but not treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Simeprevir 150 milligram 12 Weeks PR12/24
    Arm description
    Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.
    Arm type
    Experimental

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir (TMC435) 150 milligram capsule orally once daily up to week 12.

    Investigational medicinal product name
    Pegylated Interferon-2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received pegylated interferon-2a 180 microgram (mcg) administered subcutaneous injection of 0.5 mL once weekly up to week 12.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ribavirin 1000 mg or 1200 mg tablets administered orally twice daily as per subjects weight up to week 12.

    Number of subjects in period 1
    Simeprevir 150 milligram 12 Weeks PR12/24
    Started
    230
    Completed
    208
    Not completed
    22
         Subject entered another trial
    3
         Not specified
    1
         Subject non-compliant
    1
         Consent withdrawn by subject
    7
         Lost to follow-up
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Simeprevir 150 milligram 12 Weeks PR12/24
    Reporting group description
    Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.

    Reporting group values
    Simeprevir 150 milligram 12 Weeks PR12/24 Total
    Number of subjects
    230 230
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    226 226
        From 65 to 84 years
    4 4
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    47 (19 to 68) -
    Title for Gender
    Units: subjects
        Female
    91 91
        Male
    139 139

    End points

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    End points reporting groups
    Reporting group title
    Simeprevir 150 milligram 12 Weeks PR12/24
    Reporting group description
    Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.

    Subject analysis set title
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.

    Subject analysis set title
    Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.

    Primary: Percentage Of Subjects Infected With Genotype 1 hepatitis C virus (HCV) With A Sustained Virologic Response 12 Weeks (SVR12)

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    End point title
    Percentage Of Subjects Infected With Genotype 1 hepatitis C virus (HCV) With A Sustained Virologic Response 12 Weeks (SVR12) [1]
    End point description
    Sustained Virologic Response (SVR) 12 is defined as the percentage of subjects (ITT analysis set) genotype 1 hepatitis C virus (HCV) ribonucleic acid (RNA) levels less than (<) 25 International unit per milliliter (IU/mL) detectable or undetectable at 12 weeks. The Intent to treat (ITT) population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Primary
    End point timeframe
    Up to Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been reported for this endpoint based on the comparison of the response rate in the genotype 1-infected subjects who received a 12-week treatment with the minimally acceptable response rate of 80%.
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1
    Number of subjects analysed
    123
    Units: Percentage Of Subjects
        number (confidence interval 95%)
    65.9 (57.47 to 74.23)
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects Infected With Genotype 4 HCV With A Sustained Virologic Response 12 Weeks (SVR12)

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    End point title
    Percentage Of Subjects Infected With Genotype 4 HCV With A Sustained Virologic Response 12 Weeks (SVR12)
    End point description
    SVR 12 is defined as the percentage of subjects (ITT analysis set) genopype 4 HCV RNA levels < 25 IU/mL detectable or undetectable at 12 weeks. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    34
    Units: Percentage of Subjects
        number (confidence interval 95%)
    97.1 (91.38 to 100)
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects Achieved Rapid Virologic Response (RVR)

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    End point title
    Percentage Of Subjects Achieved Rapid Virologic Response (RVR)
    End point description
    Rapid virologic response (RVR) defined as HCV RNA < 25 IU/mL undetectable measured 4 weeks after start of treatment. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 4
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    162 [2]
    66 [3]
    Units: Subjects
    number (not applicable)
        12 Weeks Treatment
    100
    100
        > 12 (24/48) Weeks Treatment
    12.8
    75
    Notes
    [2] - Subjects enrolled are 123 up to week 12 and 39 for more than (>)12 (24/48) Weeks.
    [3] - Subjects enrolled are 34 up to week 12 and 32 for more than (>)12 (24/48) Weeks.
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects Achieved Virologic Response At Week 2 (W2VR)

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    End point title
    Percentage Of Subjects Achieved Virologic Response At Week 2 (W2VR)
    End point description
    Virologic response at Week 2 (W2VR) defined as HCV RNA < 25 IU/mL (detectable or undetectable) measured 2 weeks after start of treatment. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 2
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    122
    34
    Units: Percentage Of Subjects
    number (not applicable)
        < 25 undetectable: 12 weeks
    41.8
    94.1
        < 25 undetectable: >12 weeks
    5.1
    0
        < 25 detectable: 12 weeks
    58.2
    5.9
        < 25 detectable: >12 weeks
    17.9
    71
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects With Sustained Virologic Response 24 Weeks After Planned End Of Treatment (SVR24)

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    End point title
    Percentage Of Subjects With Sustained Virologic Response 24 Weeks After Planned End Of Treatment (SVR24)
    End point description
    SVR 24 is defined as the percentage of subjects (ITT analysis set) HCV RNA levels less than < 25 IU/mL detectable or undetectable at 24 weeks after the end of treatment. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    163 [4]
    67 [5]
    Units: Percentage of Subjects
    number (confidence interval 95%)
        12 Weeks Treatment
    64.2 (55.76 to 72.7)
    97.1 (91.38 to 100)
        > 12 (24/48) Weeks Treatment
    52.5 (37.02 to 67.98)
    81.8 (68.66 to 94.98)
    Notes
    [4] - Subjects enrolled are 123 up to week 12 and 40 for more than (>)12 (24/48) Weeks.
    [5] - Subjects enrolled are 34 up to week 12 and 33 for more than (>)12 (24/48) Weeks.
    No statistical analyses for this end point

    Secondary: Hepatitis C Virus (HCV) RNA At Each Time Point

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    End point title
    Hepatitis C Virus (HCV) RNA At Each Time Point
    End point description
    The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir). n is defined as number of subjects analysed for this endpoint at specific timepoint. EOT is defined as the end of treatment at week 48.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    163
    67
    Units: Number of Subjects
    arithmetic mean (standard deviation)
        Baseline (n=163, 67)
    5201191 ± 6560084
    2892674 ± 4889401
        Week 1 (n=162, 65)
    4149.6 ± 50035.91
    245.3 ± 881.88
        Week 2 (n=161, 65)
    392.5 ± 3103.04
    6875.9 ± 55191.74
        Week 4 (n=162, 66)
    1124.9 ± 9931.98
    6693.4 ± 54281.9
        Week 8 (n=154, 64)
    9.3 ± 2.08
    9.2 ± 1.88
        Week 12 (n=147, 61)
    9 ± 0
    9 ± 0
        Week 16 (n=29, 27)
    13663.9 ± 73533.68
    9 ± 0
        Week 20 (n=29, 26)
    31767.3 ± 171023.7
    9 ± 0
        Week 24 (n=26, 22)
    9 ± 0
    9 ± 0
        EOT (n=162, 66)
    6806.3 ± 72951.22
    6692.1 ± 54282.07
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects With Viral Breakthrough

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    End point title
    Percentage Of Subjects With Viral Breakthrough
    End point description
    Viral breakthrough is a confirmed increase of more than (>) 1 log10 IU/mL in HCV RNA level from the lowest level reached, or a confirmed HCV RNA level of > 100 IU/mL in subjects whose HCV RNA levels had previously been below the limit of quantification (< 25 IU/mL detectable or undetectable) while on study treatment. The Viral Breakthrough during triple therapy or PR phase includes ITT Population with randomized subjects received at least 1 dose of study drug (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    163 [6]
    67 [7]
    Units: Percentage of Subjects
    number (not applicable)
        12 Weeks Treatment
    0
    0
        >12 Weeks Treatment
    10.3
    3.1
    Notes
    [6] - Subjects enrolled are 123 up to week 12 and 40 for more than (>)12 (24/48) Weeks.
    [7] - Subjects enrolled are 34 up to week 12 and 33 for more than (>)12 (24/48) Weeks.
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects With Viral Relapse

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    End point title
    Percentage Of Subjects With Viral Relapse
    End point description
    Subjects considered to have a viral relapse if at actual end of treatment HCV RNA levels < 25 IU/mL undetectable, and during the follow-up period HCV RNA levels > or = 25 IU/mL. The ITT population included all randomized subjects who received at least 1 dose of study drud (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    163 [8]
    67 [9]
    Units: Percentage of Subjects
    number (not applicable)
        12 Weeks Treatment
    34.4
    2.9
        > 12 Weeks Treatment
    30
    10
    Notes
    [8] - Subjects enrolled are 123 up to week 12 and 40 for more than (>)12 (24/48) Weeks.
    [9] - Subjects enrolled are 34 up to week 12 and 33 for more than (>)12 (24/48) Weeks.
    No statistical analyses for this end point

    Secondary: Change From Baseline In The Hepatitis C Treatment Symptom and Impact Questionnaire (HCV SIQ) Symptom And Impact Scores

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    End point title
    Change From Baseline In The Hepatitis C Treatment Symptom and Impact Questionnaire (HCV SIQ) Symptom And Impact Scores
    End point description
    The HCV SIQ asks subjects to rate 26 symptoms associated with HCV or its treatment and how symptoms impacted the subjects life during the prior week. Total Symptom Score [symptom items 1-26 were rescaled from 0 (none) to 100 (maximum severity/frequency) with a total score calculated from the mean of all symptoms] and Body System Scores [symptom items 1-26 were rescaled from 0 (none) to 100 (maximum severity/frequency) with domain scores calculated for each body system based on mean items scores within each domain. The overall body system score is then calculated as mean of the domain scores] were calculated and analyzed for HCV SIQ. The ITT population included all randomized subjects who received at least 1 dose of study drug (SMV) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The value 99999 indicates standard deviation cannot be determined as only one subject analyzed at this time point.
    End point type
    Secondary
    End point timeframe
    Day 1 and at each study visit up to Week 72
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    230
    Units: Number of Subjects
    arithmetic mean (standard deviation)
        Baseline (n=212)
    8.9 ± 9.33
        Week 1 (n=205)
    13.8 ± 11.18
        Week 2 (n=201)
    15.6 ± 12.55
        Week 4 (n=204)
    20.1 ± 14.58
        Week 8 (n=214)
    23 ± 15.96
        Week 12 (n=195)
    25.5 ± 17.86
        Week 16 (n=204)
    16.6 ± 14.78
        Week 20 (n=184)
    14.8 ± 14.07
        Week 24 (n=202)
    14.1 ± 14.38
        Week 28 (n=49)
    13.3 ± 13.17
        Week 36 (n=192)
    9.1 ± 10.49
        Week 48 (n=50)
    8.5 ± 11.02
        Week 52 (n=1)
    4.8 ± 99999
        Week 60 (n=1)
    5.8 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline In The Fatigue Severity Scale (FSS) Total Score

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    End point title
    Change From Baseline In The Fatigue Severity Scale (FSS) Total Score
    End point description
    The FSS was used to document fatigue severity and impact of fatigue on subjects daily lives. Fatigue severity was measured using the FSS score, created as the mean of patient ratings for 9 items in the Fatigue Severity Scale. FSS scores have a range from 1 to 7 where higher scores indicate more severe fatigue. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is number of subjects analysed at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 and at each study visit up to Week 72
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    230
    Units: Number of Subjects
    arithmetic mean (standard deviation)
        Baseline (n=226)
    2.733 ± 1.5692
        Week 4 (n=219)
    3.736 ± 1.8846
        Week 8 (n=218)
    3.916 ± 1.9206
        Week 12 (n=208)
    4.085 ± 1.9339
        Week 16 (n=207)
    3.153 ± 1.789
        Week 20 (n=51)
    3.903 ± 1.9175
        Week 24 (n=196)
    2.583 ± 1.5983
        Week 36 (n=197)
    2.443 ± 1.5463
        Week 48 (n=52)
    2.268 ± 1.5064
        Week 60 (n=1)
    3.778 ± 99999
        Week 72 (n=1)
    2.667 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline In The Center For Epidemiologic Studies Depression Scale (CES-D) Score

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    End point title
    Change From Baseline In The Center For Epidemiologic Studies Depression Scale (CES-D) Score
    End point description
    The Center For Epidemiologic Studies Depression Scale (CES-D) is the scores (0-3) for each of the 20 individual items are summed up to yield a total score (0 -60) with higher scores indicating more and/or more frequent experience of depressive symptoms during the past week. The scores of 16 to 22 indicate mild to moderate depressive illness and CES-D scores more than or equal to (≥) 23 indicate probable major depressive illness (sensitivity: 0.95, specificity: 0.29). The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is 'number of subjects' analysed in this endpoint at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 and at each study visit up to Week 72
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    230
    Units: Number of subjects
    arithmetic mean (standard deviation)
        Baseline (n=228)
    11 ± 7.79
        Week 4 (n=218)
    15.7 ± 10.41
        Week 8 (n=213)
    15.8 ± 10.45
        Week 12 (n=213)
    17.3 ± 11.69
        Week 16 (n=205)
    12.5 ± 10.37
        Week 20 (n=50)
    15.2 ± 10.16
        Week 24 (n=200)
    10.8 ± 8.94
        Week 36 (n=192)
    9.2 ± 8.86
        Week 48 (n=52)
    9 ± 7.8
        Week 60 (n=1)
    4 ± 99999
        Week 72 (n=1)
    6 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline In The Work Productivity And Activity Index (WPAI) For Hepatitis C Missed Work Time, Daily Activity Impairment And Productivity Scores

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    End point title
    Change From Baseline In The Work Productivity And Activity Index (WPAI) For Hepatitis C Missed Work Time, Daily Activity Impairment And Productivity Scores
    End point description
    The Work Productivity And Activity Index (WPAI) was used to measure the impact of HCV on time missed from work (absenteeism), reduced performance while at work (productivity impairment), and impairment in daily activities without regard to employment status. The WPAI Productivity score has a possible range from 0% to 100% with higher scores indicating greater impairment in productivity. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is 'number of subjects' analysed for this endpoint at specific timepoints.
    End point type
    Secondary
    End point timeframe
    Day 1 and at each study visit up to Week 72
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    230
    Units: Number of subjects
    arithmetic mean (standard deviation)
        Baseline (n=106)
    8.3 ± 16.94
        Week 4 (n=94)
    32.3 ± 32.89
        Week 8 (n=96)
    30.1 ± 31.34
        Week 12 (n=89)
    37.9 ± 34.48
        Week 16 (n=92)
    22.7 ± 31.54
        Week 20 (n=19)
    35.8 ± 37.77
        Week 24 (n=100)
    13.8 ± 24.57
        Week 36 (n=79)
    8.9 ± 18.17
        Week 48 (n=25)
    7.2 ± 12.99
        Week 60 (n=1)
    0 ± 99999
        Week 72 (n=1)
    0 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline In The EuroQol 5 Dimension (EQ5D) Visual Analog Scale (VAS) Valuation Index And Descriptive System Scores

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    End point title
    Change From Baseline In The EuroQol 5 Dimension (EQ5D) Visual Analog Scale (VAS) Valuation Index And Descriptive System Scores
    End point description
    The EQ-5D questionnaire is an instrument designed to assess overall health status using 5 health dimension scores (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and a "thermometer" visual analog scale (VAS) ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir) and completed 5 questionnaires during study visits at baseline, throughout treatment and follow-up to document changes. The data value 99999 indicate that standard deviation cannot be determined as only one subject analyzed at this time point. n is'number of subjects' analysed for this endpoint at specific timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 and at each study visit up to Week 72
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    230
    Units: Number of subjects
    arithmetic mean (standard deviation)
        Baseline (n=197)
    81.4 ± 16.41
        Week 4 (n=189)
    71.6 ± 20.06
        Week 8 (n=193)
    73.4 ± 17.7
        Week 12 (n=201)
    73.1 ± 19.5
        Week 16 (n=200)
    79.9 ± 17.43
        Week 20 (n=47)
    71.2 ± 20.08
        Week 24 (n=192)
    82 ± 16.01
        Week 36 (n=191)
    85.9 ± 14.62
        Week 48 (n=47)
    87.3 ± 10.72
        Week 60 (n=1)
    95 ± 99999
        Week 72 (n=1)
    95 ± 99999
    No statistical analyses for this end point

    Secondary: The Percentage Of Subjects With Normalized Alanine Aminotransferase (ALT) Levels

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    End point title
    The Percentage Of Subjects With Normalized Alanine Aminotransferase (ALT) Levels
    End point description
    The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    115
    Units: Percentage of Subjects
        number (not applicable)
    85.2
    No statistical analyses for this end point

    Secondary: Percentage Of Subjects With Sustained Virologic Response 12 Weeks After Planned End Of Treatment (SVR12)

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    End point title
    Percentage Of Subjects With Sustained Virologic Response 12 Weeks After Planned End Of Treatment (SVR12)
    End point description
    SVR 12 is defined as the percentage of subjects (ITT analysis set) HCV RNA levels less than < 25 IU/mL detectable or undetectable at 12 weeks after the end of treatment. Subjects with HCV RNA <25 detectable or undetectable at 2 Weeks and <25 undetectable at 4 Weeks and <25 undetectable at 8 Weeks meet the Response Guided Treatment (RGT) criteria. Subjects that meet the RGT criteria have a planned treatment duration of 12 Weeks, whereas subjects who do not meet this rule have a planned treatment duration of 24 (or 48) weeks The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir). The value 000 or 999 indicates that no data evaluated at this timepoint.
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    Simeprevir 12Wks 150 mg PR12/24: Genotype 1 Simeprevir 12Wks 150 mg PR12/24: Genotype 4
    Number of subjects analysed
    163 [10]
    67 [11]
    Units: subjects
    number (confidence interval 95%)
        Met RGT criteria: 12 weeks Treatment
    75.5 (0 to 999)
    50.7 (0 to 999)
        SVR12: Met RGT criteria: >12 weeks Treatment
    65.9 (57.47 to 74.23)
    97.1 (91.38 to 100)
        Did not Met RGT criteria: 12 weeks treatment
    23.3 (0 to 999)
    46.3 (0 to 999)
        SVR12:Did not Met RGT criteria:>12 weeks treatment
    55.3 (39.45 to 71.07)
    83.9 (70.92 to 96.82)
    Notes
    [10] - N includes number of subjects analysed to evaluate RGT Criteria.
    [11] - N includes number of subjects analysed to evaluate RGT Criteria.
    No statistical analyses for this end point

    Secondary: The Number Of Subjects Reporting Adverse Events

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    End point title
    The Number Of Subjects Reporting Adverse Events
    End point description
    All subjects will be monitored throughout the study for the occurrence of adverse events including psychiatric symptoms, anemia, hyperglycemia (elevated glucose levels), disturbances in serum creatinine levels (a measure of renal [kidney] safety), decreased White Blood Cell (WBC) Count, decreased Platelet Count (ability of the blood to clot), and thyroid abnormalities. The ITT population included all randomized subjects who received at least 1 dose of investigational medication (Simeprevir).
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Simeprevir 150 milligram 12 Weeks PR12/24
    Number of subjects analysed
    230
    Units: Number of Subjects
        SMV+PR Phase (n=230)
    213
        PR Phase (n=62)
    40
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 48 weeks
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Simeprevir 150 milligram 12 Weeks PR12/24
    Reporting group description
    Subjects received a 12-week triple therapy with Simeprevir (TMC435) 150 milligram (mg) plus pegylated interferon (PegIFNa-2a) and ribavirin (RBV) in treatment-naïve adult subjects with genotype 1 or genotype 4 chronic hepatitis C virus (HCV) infection and fibrosis stage equivalent to F0-F2. Treatment Extension up to 24/48 weeks total treatment duration was response-guided based on HCV RNA levels at Week 2, Week 4, and Week 8.

    Serious adverse events
    Simeprevir 150 milligram 12 Weeks PR12/24
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 230 (3.48%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Testicular necrosis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Furuncle
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericoronitis
         subjects affected / exposed
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Simeprevir 150 milligram 12 Weeks PR12/24
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    204 / 230 (88.70%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    23 / 230 (10.00%)
         occurrences all number
    23
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    48 / 230 (20.87%)
         occurrences all number
    80
    Anaemia
         subjects affected / exposed
    26 / 230 (11.30%)
         occurrences all number
    28
    Nervous system disorders
    Headache
         subjects affected / exposed
    54 / 230 (23.48%)
         occurrences all number
    60
    Dizziness
         subjects affected / exposed
    13 / 230 (5.65%)
         occurrences all number
    13
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    12 / 230 (5.22%)
         occurrences all number
    13
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    59 / 230 (25.65%)
         occurrences all number
    64
    Influenza like illness
         subjects affected / exposed
    71 / 230 (30.87%)
         occurrences all number
    85
    Asthenia
         subjects affected / exposed
    57 / 230 (24.78%)
         occurrences all number
    61
    Pyrexia
         subjects affected / exposed
    27 / 230 (11.74%)
         occurrences all number
    29
    Irritability
         subjects affected / exposed
    15 / 230 (6.52%)
         occurrences all number
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    31 / 230 (13.48%)
         occurrences all number
    31
    Depression
         subjects affected / exposed
    20 / 230 (8.70%)
         occurrences all number
    20
    Sleep disorder
         subjects affected / exposed
    17 / 230 (7.39%)
         occurrences all number
    18
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    24 / 230 (10.43%)
         occurrences all number
    26
    Nausea
         subjects affected / exposed
    20 / 230 (8.70%)
         occurrences all number
    24
    Vomiting
         subjects affected / exposed
    13 / 230 (5.65%)
         occurrences all number
    13
    Abdominal pain upper
         subjects affected / exposed
    12 / 230 (5.22%)
         occurrences all number
    12
    Dry mouth
         subjects affected / exposed
    12 / 230 (5.22%)
         occurrences all number
    12
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    71 / 230 (30.87%)
         occurrences all number
    80
    Dry skin
         subjects affected / exposed
    33 / 230 (14.35%)
         occurrences all number
    37
    Rash
         subjects affected / exposed
    34 / 230 (14.78%)
         occurrences all number
    44
    Erythema
         subjects affected / exposed
    12 / 230 (5.22%)
         occurrences all number
    14
    Alopecia
         subjects affected / exposed
    15 / 230 (6.52%)
         occurrences all number
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 230 (9.13%)
         occurrences all number
    23
    Myalgia
         subjects affected / exposed
    18 / 230 (7.83%)
         occurrences all number
    23
    Back pain
         subjects affected / exposed
    13 / 230 (5.65%)
         occurrences all number
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    36 / 230 (15.65%)
         occurrences all number
    37

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2013
    The overall reason for the amendment was to implement comments received from ethics committees (EC) and Health authorities (HA) and to update the benefit-risk assessment with Phase 3 data that had become available.
    28 Oct 2013
    The overall reason for the amendment was to introduce precautionary language on photosensitivity.
    02 Dec 2013
    The overall reason for the amendment was to include subjects with genotype 4 hepatitis C virus (HCV) infection in the trial population.
    16 Jun 2014
    This amendment was created as an urgent safety measure because, in the ongoing study, a higher than expected relapse rate was observed in subjects infected with HCV genotype 1 and with a host interleukin-28B (IL28B) genotype CT or TT, who had detectable HCV Ribonucleic acid (RNA) at week 2.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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