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    Clinical Trial Results:
    An Open-Label, Single-Arm Phase III Study to Evaluate the Efficacy, Safety and Tolerability of TMC435 in Combination With PegIFN alfa-2a (Pegasys) and Ribavirin (Copegus) in Treatment-Naive or Treatment-Experienced, Chronic Hepatitis C Virus Genotype-4 Infected participants.

    Summary
    EudraCT number
    2011-004097-29
    Trial protocol
    BE  
    Global end of trial date
    20 Mar 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Jun 2016
    First version publication date
    20 Jun 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC435HPC3011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01567735
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen R&D Ireland
    Sponsor organisation address
    Eastgate Village,Eastgate, Little Island, Co. Cork, Ireland,
    Public contact
    Clinical Registry Group, Janssen Research & Development, +353 21 4673500, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, +353 21 4673500, 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
    20 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of TMC435 in combination with PegIFNα-2a/RBV with respect to the proportion of participants with chronic HCV-4 infection achieving SVR 12 weeks after planned end of treatment (SVR12) in the overall population as well as in the different subpopulations (treatment-naive, previous relapsers and previous nonresponders).
    Protection of trial subjects
    Safety and tolerability were evaluated throughout the study by monitoring of adverse events (AEs), performing laboratory tests, monitoring of adverse events (AEs),measurement of vital signs, electrocardiogram and performing physical examinations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 38
    Country: Number of subjects enrolled
    France: 69
    Worldwide total number of subjects
    107
    EEA total number of subjects
    107
    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)
    100
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted from 16 February 2012 to 20 March 2014.

    Pre-assignment
    Screening details
    136 participants were screened of whom 107 participants were treated and 103 participants completed the study.

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

    Arms
    Arm title
    simeprevir (TMC435)
    Arm description
    Participants received TMC435 150 mg once daily plus peginterferon alfa-2a (PegIFN alfa-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFN alfa-2a (P) and RBV (R) until Week 24/48 (PR24/48). Treatment was to be stopped at Week 24 for HCV treatment-naive and prior HCV relapsers who met the response guided therapy criteria. All prior HCV non-responders (null and partial), and HCV treatment-naive and prior HCV relapsers who did not meet the response guided therapy criteria had a 48-week treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    simeprevir
    Investigational medicinal product code
    TMC435
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received TMC435 150 mg once daily plus peginterferon alfa-2a (PegIFN alfa-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFN alfa-2a (P) and RBV (R) until Week 24/48 (PR24/48). Treatment was to be stopped at Week 24 for HCV treatment-naive and prior HCV relapsers who met the response guided therapy criteria. All prior HCV non-responders (null and partial), and HCV treatment-naive and prior HCV relapsers who did not meet the response guided therapy criteria had a 48-week treatment period.

    Number of subjects in period 1
    simeprevir (TMC435)
    Started
    107
    Completed
    103
    Not completed
    4
         Consent withdrawn by subject
    1
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    simeprevir (TMC435)
    Reporting group description
    Participants received TMC435 150 mg once daily plus peginterferon alfa-2a (PegIFN alfa-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFN alfa-2a (P) and RBV (R) until Week 24/48 (PR24/48). Treatment was to be stopped at Week 24 for HCV treatment-naive and prior HCV relapsers who met the response guided therapy criteria. All prior HCV non-responders (null and partial), and HCV treatment-naive and prior HCV relapsers who did not meet the response guided therapy criteria had a 48-week treatment period.

    Reporting group values
    simeprevir (TMC435) Total
    Number of subjects
    107 107
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    100 100
        From 65 to 84 years
    7 7
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    49 (27 to 69) -
    Title for Gender
    Units: subjects
        Female
    23 23
        Male
    84 84

    End points

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    End points reporting groups
    Reporting group title
    simeprevir (TMC435)
    Reporting group description
    Participants received TMC435 150 mg once daily plus peginterferon alfa-2a (PegIFN alfa-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFN alfa-2a (P) and RBV (R) until Week 24/48 (PR24/48). Treatment was to be stopped at Week 24 for HCV treatment-naive and prior HCV relapsers who met the response guided therapy criteria. All prior HCV non-responders (null and partial), and HCV treatment-naive and prior HCV relapsers who did not meet the response guided therapy criteria had a 48-week treatment period.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) population, which includes all participants who took at least 1 dose of study medication.

    Primary: Percentage of participants achieving sustained virologic response 12 weeks after planned end of treatment (SVR12)

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    End point title
    Percentage of participants achieving sustained virologic response 12 weeks after planned end of treatment (SVR12) [1]
    End point description
    Participants are considered to have reached SVR12 if both conditions below are met: 1) HCV RNA levels less than (<) 25 International unit per milliliter (IU/mL) undetectable at the actual end of treatment; 2) HCV RNA levels <25 IU/mL undetectable or HCV RNA levels <25 IU/mL detectable 12 weeks after planned end of treatment. SVR 12 was reported for overall population (that is, ITT population), treatment naive, relapser and non-responder participants. 'N' (number of participants analyzed) signifies the participants evaluable for this measure and "n" signifies those participants who were evaluated for this measure at the specified time point.
    End point type
    Primary
    End point timeframe
    12 Weeks After the Planned End of Treatment (Planned EOT: if participant eligible for response-guided treatment (RGT) and met the criteria: Week 24; otherwise Week 48)
    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 statistics were done, no inferential statistical analyses were performed
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    107 [2]
    Units: Percentage of participants
    number (not applicable)
        Overall SVR12 (n=107)
    65.4
        Treatment naive (n=35)
    82.9
        Relapser(n=22)
    86.4
        Non-Responder(n=50)
    44
    Notes
    [2] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving sustained virologic response 4 weeks after planned end of treatment (SVR4)

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    End point title
    Percentage of participants achieving sustained virologic response 4 weeks after planned end of treatment (SVR4)
    End point description
    Participants are considered to have reached SVR4 and SVR 12 if both conditions below are met: 1) HCV RNA levels less than <25 International unit per milliliter (IU/mL) undetectable (at the actual end of treatment);2) HCV RNA levels <25 IU/mL undetectable or HCV RNA levels <25 IU/mL detectable (4, 12, 24, 36 and 48 weeks after the planned EOT).
    End point type
    Secondary
    End point timeframe
    4 weeks after Planned EOT (if participant eligible for response-guided treatment (RGT) and met the criteria: Week 24; otherwise Week 48)
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    107 [3]
    Units: Percentage of Participants
        number (not applicable)
    68.2
    Notes
    [3] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving sustained virologic response 24 weeks after planned end of treatment (SVR24).

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    End point title
    Percentage of participants achieving sustained virologic response 24 weeks after planned end of treatment (SVR24).
    End point description
    Participants are considered to have reached SVR24 if both conditions below are met: 1) HCV RNA levels less than <25 International units per milliliter (IU/mL) undetectable (at the actual end of treatment);2) HCV RNA levels <25 IU/mL undetectable or HCV RNA levels <25 IU/mL detectable (24 weeks after the planned EOT.
    End point type
    Secondary
    End point timeframe
    24 Weeks After the Planned EOT (if participant eligible for response-guided treatment (RGT) and met the criteria: Week 24; otherwise Week 48
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    107 [4]
    Units: Percentage of participants
        number (not applicable)
    65.4
    Notes
    [4] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With On-treatment Virologic Failure

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    End point title
    Percentage of Participants With On-treatment Virologic Failure
    End point description
    Participants were considered as an on-treatment failure if, at actual end of treatment (EOT), there was confirmed detectable HCV RNA levels.
    End point type
    Secondary
    End point timeframe
    Actual EOT (Week 24 or Week 48 or Early withdrawal)
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    107 [5]
    Units: percentage of participants
        number (not applicable)
    23.4
    Notes
    [5] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Viral Breakthrough

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    End point title
    Percentage of Participants With Viral Breakthrough
    End point description
    Viral breakthrough was defined as a confirmed increase of more than 1 log10 in Hepatitis C Virus (HCV) ribonucleic acid (RNA) level from the lowest level reached or a confirmed value of HCV RNA more than 100 international units/milliliter (IU/mL) in participants whose HCV RNA was previously less than 25 IU/mL.
    End point type
    Secondary
    End point timeframe
    Up to Actual EOT (Week 24 or Week 48 or Early withdrawal)
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    107 [6]
    Units: percentage of participants
        number (not applicable)
    18.7
    Notes
    [6] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Viral Relapse

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    End point title
    Percentage of Participants With Viral Relapse
    End point description
    Participants are considered to have a viral relapse if both conditions as specified are met: 1) <25 IU/mL undetectable HCV RNA at the actual end of study drug treatment; 2) confirmed HCV RNA greater than or equal to (>=) 25 IU/mL during follow-up. ‘N’ (number of participants analyzed) signifies those participants who were evaluable for this measure. The incidence of viral relapse is only calculated for subjects with undetectable HCV RNA levels (or unconfirmed detectable) at EOT and with at least one follow-up HCV RNA measurement.
    End point type
    Secondary
    End point timeframe
    Actual EOT (Week 24 or Week 48 or Early withdrawal) upto end of follow up period
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    82
    Units: percentage of participants
        number (not applicable)
    14.6
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
    End point type
    Secondary
    End point timeframe
    Upto End of treatment (EOT:week 48)
    End point values
    simeprevir (TMC435)
    Number of subjects analysed
    107 [7]
    Units: Participants
    number (not applicable)
        AEs
    104
        SAEs
    8
    Notes
    [7] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to End of Treatment (EOT: Week 24 or Week 48 or Early Withdrawal)
    Adverse event reporting additional description
    Adverse events were reported for the entire treatment phase.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Simeprevir(TMC435)
    Reporting group description
    Participants received TMC435 150 mg once daily plus peginterferon alfa-2a (PegIFN alfa-2a) and ribavirin (RBV) for 12 Weeks (Wks) followed by PegIFN alfa-2a (P) and RBV (R) until Week 24/48 (PR24/48). Treatment was to be stopped at Week 24 for HCV treatment-naive and prior HCV relapsers who met the response guided therapy criteria. All prior HCV non-responders (null and partial), and HCV treatment-naive and prior HCV relapsers who did not meet the response guided therapy criteria had a 48-week treatment period.

    Serious adverse events
    Simeprevir(TMC435)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 107 (7.48%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spondylitic myelopathy
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 107 (0.93%)
         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(TMC435)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 107 (97.20%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 107 (16.82%)
         occurrences all number
    21
    Leukopenia
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    7
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    20 / 107 (18.69%)
         occurrences all number
    20
    Epistaxis
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    7
    Cough
         subjects affected / exposed
    23 / 107 (21.50%)
         occurrences all number
    26
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 107 (26.17%)
         occurrences all number
    34
    Dizziness
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    7
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    11 / 107 (10.28%)
         occurrences all number
    11
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    51 / 107 (47.66%)
         occurrences all number
    56
    Chills
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Asthenia
         subjects affected / exposed
    49 / 107 (45.79%)
         occurrences all number
    62
    Fatigue
         subjects affected / exposed
    38 / 107 (35.51%)
         occurrences all number
    63
    Injection site erythema
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    24 / 107 (22.43%)
         occurrences all number
    26
    Mood altered
         subjects affected / exposed
    13 / 107 (12.15%)
         occurrences all number
    16
    Depression
         subjects affected / exposed
    9 / 107 (8.41%)
         occurrences all number
    14
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    9 / 107 (8.41%)
         occurrences all number
    9
    Dry mouth
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    8 / 107 (7.48%)
         occurrences all number
    8
    Nausea
         subjects affected / exposed
    11 / 107 (10.28%)
         occurrences all number
    13
    Diarrhoea
         subjects affected / exposed
    13 / 107 (12.15%)
         occurrences all number
    15
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    32 / 107 (29.91%)
         occurrences all number
    34
    Rash
         subjects affected / exposed
    13 / 107 (12.15%)
         occurrences all number
    16
    Dry skin
         subjects affected / exposed
    28 / 107 (26.17%)
         occurrences all number
    32
    Alopecia
         subjects affected / exposed
    9 / 107 (8.41%)
         occurrences all number
    9
    Erythema
         subjects affected / exposed
    9 / 107 (8.41%)
         occurrences all number
    12
    Skin lesion
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    12 / 107 (11.21%)
         occurrences all number
    12
    Arthralgia
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Back pain
         subjects affected / exposed
    10 / 107 (9.35%)
         occurrences all number
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    22 / 107 (20.56%)
         occurrences all number
    25
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 107 (6.54%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2012
    Based on consultations with Health Authorities, the following substantial changes: The definitions for SVR12 and SVR24 were evaluated and updated and it clarified that a liver biopsy is the required method for all subjects without a contraindication for this procedure.

    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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