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    Clinical Trial Results:
    A Phase III, randomized, double-blind trial to evaluate the efficacy, safety and tolerability of TMC435 vs. telaprevir, both in combination with PegIFNα-2a and ribavirin, in chronic hepatitis C genotype-1 infected subjects who were null or partial responders to prior PegIFNα and ribavirin therapy

    Summary
    EudraCT number
    2011-001180-53
    Trial protocol
    PT   GR   BE   ES   DE   SE   HU   AT   DK   PL   CZ   NO   GB   IT   BG  
    Global end of trial date
    28 Apr 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Jun 2016
    First version publication date
    31 May 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
    TMC435HPC3001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01485991
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Sciences
    Sponsor organisation address
    Eastgate Village, Eastgate, Little Island, Co. Cork, Ireland,
    Public contact
    Janssen R&D Ireland Eastgate Village, Eastgate Little Island, Co. Cork Ireland , Janssen Research & Development, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com, + 353 21 4673500, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen R&D Ireland Eastgate Village, Eastgate Little Island, Co. Cork Ireland , Janssen Research & Development, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com, + 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
    28 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to demonstrate the efficacy of TMC435 in combination with peginterferon (PegIFN) + ribavirin (RBV) by means of establishing its non- inferiority compared to an approved regimen of telaprevir + PegIFN + RBV in participants with chronic hepatitis C who have previously failed PegIFN.
    Protection of trial subjects
    Table of AEs, incidence of AEs (regardless of severity or relation to study drugs), AEs of at least Grade 3 (regardless of relation to study drugs), and incidence of treatment-emergent graded laboratory abnormalities of interest over time will be reported.
    Background therapy
    PegIFN + RBV
    Evidence for comparator
    Telaprevir
    Actual start date of recruitment
    19 Jan 2012
    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
    Argentina: 24
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 32
    Country: Number of subjects enrolled
    Brazil: 46
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Greece: 15
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Israel: 27
    Country: Number of subjects enrolled
    Italy: 49
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 91
    Country: Number of subjects enrolled
    Portugal: 19
    Country: Number of subjects enrolled
    Romania: 82
    Country: Number of subjects enrolled
    Sweden: 26
    Country: Number of subjects enrolled
    United States: 96
    Worldwide total number of subjects
    763
    EEA total number of subjects
    532
    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)
    730
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    771 participants were randomly assigned into two treatment groups,but only 763 of them received the study drug.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Arm description
    2 Telaprevir (TVR) tablets, orally, 3 times a day along with TMC435 matched placebo capsule once daily for 12 weeks, in addition to peginterferon alfa-2a and ribavirin for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    telaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 Telaprevir (TVR) tablets, orally, 3 times a day along with 150 mg TMC435 matched placebo capsule once daily for 12 weeks, in addition to peginterferon alfa-2a and ribavirin for 48 weeks.

    Arm title
    Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Arm description
    Simeprevir (TMC435) capsule, orally, once daily for 12 weeks, along with 2 telaprevir (TVR) matched placebo tablets 3 times a day for 12 weeks, and peginterferon alfa-2a and ribavirin for 48 weeks.
    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
    Simeprevir (TMC435) 150 milligram (mg) capsule, orally, once daily for 12 weeks, along with 2 telaprevir (TVR) matched placebo tablets 3 times a day for 12 weeks, and peginterferon alfa-2a and ribavirin for 48 weeks.

    Number of subjects in period 1
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Started
    384
    379
    Completed
    350
    353
    Not completed
    34
    26
         Adverse event
    4
    -
         Consent withdrawn by subject
    20
    13
         Lost to follow-up
    10
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Reporting group description
    2 Telaprevir (TVR) tablets, orally, 3 times a day along with TMC435 matched placebo capsule once daily for 12 weeks, in addition to peginterferon alfa-2a and ribavirin for 48 weeks.

    Reporting group title
    Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Reporting group description
    Simeprevir (TMC435) capsule, orally, once daily for 12 weeks, along with 2 telaprevir (TVR) matched placebo tablets 3 times a day for 12 weeks, and peginterferon alfa-2a and ribavirin for 48 weeks.

    Reporting group values
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Total
    Number of subjects
    384 379 763
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    364 366 730
        From 65 to 84 years
    20 13 33
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    52 (20 to 69) 50 (18 to 69) -
    Title for Gender
    Units: subjects
        Female
    161 136 297
        Male
    223 243 466

    End points

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    End points reporting groups
    Reporting group title
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Reporting group description
    2 Telaprevir (TVR) tablets, orally, 3 times a day along with TMC435 matched placebo capsule once daily for 12 weeks, in addition to peginterferon alfa-2a and ribavirin for 48 weeks.

    Reporting group title
    Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Reporting group description
    Simeprevir (TMC435) capsule, orally, once daily for 12 weeks, along with 2 telaprevir (TVR) matched placebo tablets 3 times a day for 12 weeks, and peginterferon alfa-2a and ribavirin for 48 weeks.

    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 included all randomized participants who took at least 1 dose of study medication.

    Primary: Percentage of Participants With Sustained Virologic Response 12 Weeks After the Planned End of Treatment (SVR12)

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    End point title
    Percentage of Participants With Sustained Virologic Response 12 Weeks After the Planned End of Treatment (SVR12)
    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.
    End point type
    Primary
    End point timeframe
    12 Weeks After the Planned End of Treatment (EOT: Week 48)
    End point values
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Number of subjects analysed
    384 [1]
    379 [2]
    Units: percentage of participants
        number (not applicable)
    54.7
    53.6
    Notes
    [1] - ITT population
    [2] - ITT population
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin v Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Number of subjects included in analysis
    763
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    Stratified Cochran-Mantel-Haenszel
    Parameter type
    Difference in proportions
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.8
         upper limit
    5.5

    Secondary: Percentage of Participants With Sustained Virologic Response 24 Weeks After the Planned End of Treatment (SVR24)

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    End point title
    Percentage of Participants With Sustained Virologic Response 24 Weeks After the 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 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 (24 weeks after the planned EOT).
    End point type
    Secondary
    End point timeframe
    24 Weeks After the Planned EOT (Week 48)
    End point values
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Number of subjects analysed
    384 [3]
    379 [4]
    Units: percentage of participants
        number (not applicable)
    55.2
    53.3
    Notes
    [3] - ITT population
    [4] - 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
    End of Treatment (Week 48) up to Follow-up Period (until Week 72)
    End point values
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Number of subjects analysed
    256
    246
    Units: percentage of participants
        number (not applicable)
    16.4
    17.9
    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 48)
    Adverse event reporting additional description
    Out of four deaths reported, one death occurred in the follow up phase.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Reporting group description
    2 Telaprevir tablets are taken 3 times a day together with 150 mg Simeprevir placebo capsule once daily for 12 weeks, in addition to peginterferon alfa-2a and ribavirin for 48 weeks

    Reporting group title
    Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Reporting group description
    Simeprevir capsule (150 mg) is taken once daily in addition to 2 Telaprevir placebo tablets 3 times a day for 12 weeks, in addition to peginterferon alfa-2a and ribavirin for 48 weeks

    Serious adverse events
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 384 (14.06%)
    22 / 379 (5.80%)
         number of deaths (all causes)
    4
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 384 (0.52%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic neoplasm malignant
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical peritonitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    16 / 384 (4.17%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    20 / 22
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 384 (0.78%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 384 (0.26%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic vein thrombosis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 384 (0.00%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Critical illness polyneuropathy
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mononeuropathy
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug rash with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 384 (1.04%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 384 (0.26%)
    2 / 379 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection
         subjects affected / exposed
    0 / 384 (0.00%)
    1 / 379 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candidiasis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 384 (0.26%)
    0 / 379 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Telaprevir+Placebo+Peginterferon Alfa-2a+Ribavirin Simeprevir+Placebo+Peginterferon Alfa-2a+Ribavirin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    369 / 384 (96.09%)
    349 / 379 (92.08%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    53 / 384 (13.80%)
    66 / 379 (17.41%)
         occurrences all number
    61
    76
    Dyspnoea
         subjects affected / exposed
    40 / 384 (10.42%)
    30 / 379 (7.92%)
         occurrences all number
    47
    31
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    78 / 384 (20.31%)
    82 / 379 (21.64%)
         occurrences all number
    236
    259
    Anaemia
         subjects affected / exposed
    157 / 384 (40.89%)
    95 / 379 (25.07%)
         occurrences all number
    317
    150
    Thrombocytopenia
         subjects affected / exposed
    46 / 384 (11.98%)
    40 / 379 (10.55%)
         occurrences all number
    91
    81
    Nervous system disorders
    Headache
         subjects affected / exposed
    120 / 384 (31.25%)
    103 / 379 (27.18%)
         occurrences all number
    177
    140
    Dysgeusia
         subjects affected / exposed
    36 / 384 (9.38%)
    15 / 379 (3.96%)
         occurrences all number
    37
    15
    Dizziness
         subjects affected / exposed
    43 / 384 (11.20%)
    26 / 379 (6.86%)
         occurrences all number
    53
    28
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    155 / 384 (40.36%)
    132 / 379 (34.83%)
         occurrences all number
    205
    173
    Pyrexia
         subjects affected / exposed
    101 / 384 (26.30%)
    86 / 379 (22.69%)
         occurrences all number
    133
    114
    Influenza like illness
         subjects affected / exposed
    66 / 384 (17.19%)
    64 / 379 (16.89%)
         occurrences all number
    69
    69
    Asthenia
         subjects affected / exposed
    69 / 384 (17.97%)
    80 / 379 (21.11%)
         occurrences all number
    96
    108
    Injection site erythema
         subjects affected / exposed
    27 / 384 (7.03%)
    14 / 379 (3.69%)
         occurrences all number
    27
    15
    Chills
         subjects affected / exposed
    40 / 384 (10.42%)
    22 / 379 (5.80%)
         occurrences all number
    41
    25
    Psychiatric disorders
    Depression
         subjects affected / exposed
    20 / 384 (5.21%)
    35 / 379 (9.23%)
         occurrences all number
    26
    42
    Insomnia
         subjects affected / exposed
    73 / 384 (19.01%)
    53 / 379 (13.98%)
         occurrences all number
    77
    58
    Mood altered
         subjects affected / exposed
    32 / 384 (8.33%)
    35 / 379 (9.23%)
         occurrences all number
    35
    37
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    110 / 384 (28.65%)
    74 / 379 (19.53%)
         occurrences all number
    128
    85
    Diarrhoea
         subjects affected / exposed
    60 / 384 (15.63%)
    51 / 379 (13.46%)
         occurrences all number
    72
    58
    Dyspepsia
         subjects affected / exposed
    29 / 384 (7.55%)
    25 / 379 (6.60%)
         occurrences all number
    30
    27
    Abdominal pain upper
         subjects affected / exposed
    25 / 384 (6.51%)
    24 / 379 (6.33%)
         occurrences all number
    30
    28
    Vomiting
         subjects affected / exposed
    36 / 384 (9.38%)
    23 / 379 (6.07%)
         occurrences all number
    51
    27
    Constipation
         subjects affected / exposed
    10 / 384 (2.60%)
    21 / 379 (5.54%)
         occurrences all number
    10
    25
    Abdominal pain
         subjects affected / exposed
    22 / 384 (5.73%)
    11 / 379 (2.90%)
         occurrences all number
    23
    14
    Anorectal discomfort
         subjects affected / exposed
    32 / 384 (8.33%)
    10 / 379 (2.64%)
         occurrences all number
    34
    11
    Anal pruritus
         subjects affected / exposed
    42 / 384 (10.94%)
    9 / 379 (2.37%)
         occurrences all number
    42
    10
    Dry mouth
         subjects affected / exposed
    25 / 384 (6.51%)
    11 / 379 (2.90%)
         occurrences all number
    25
    11
    Haemorrhoids
         subjects affected / exposed
    38 / 384 (9.90%)
    6 / 379 (1.58%)
         occurrences all number
    43
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    100 / 384 (26.04%)
    66 / 379 (17.41%)
         occurrences all number
    138
    100
    Pruritus
         subjects affected / exposed
    179 / 384 (46.61%)
    142 / 379 (37.47%)
         occurrences all number
    244
    182
    Dry skin
         subjects affected / exposed
    30 / 384 (7.81%)
    39 / 379 (10.29%)
         occurrences all number
    33
    43
    Alopecia
         subjects affected / exposed
    59 / 384 (15.36%)
    33 / 379 (8.71%)
         occurrences all number
    60
    34
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    63 / 384 (16.41%)
    47 / 379 (12.40%)
         occurrences all number
    70
    61
    Back pain
         subjects affected / exposed
    30 / 384 (7.81%)
    18 / 379 (4.75%)
         occurrences all number
    33
    19
    Arthralgia
         subjects affected / exposed
    45 / 384 (11.72%)
    41 / 379 (10.82%)
         occurrences all number
    52
    53
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    28 / 384 (7.29%)
    3 / 379 (0.79%)
         occurrences all number
    32
    3
    Decreased appetite
         subjects affected / exposed
    64 / 384 (16.67%)
    54 / 379 (14.25%)
         occurrences all number
    69
    60
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    21 / 384 (5.47%)
    12 / 379 (3.17%)
         occurrences all number
    25
    12

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2011
    The first amendment included change of primary efficacy endpoint SVR24 for ongoing and future SMV Phase 3 trials, to SVR12. Evaluation and updating the sustained virologic response definition and specific toxicities section. Additional tests for the urine dipstick analysis were listed. Upper age limit of 70 years for all participants was added, exclusion criteria 10 was revised. It was clarified that a liver biopsy was the required method for all subjects without a contraindication for this procedure. Clarifications were made to the disallowed concomitant medication section by adjusting the wording. Female subjects of male participants did not have to perform a pregnancy test. In the initial Clinical Trial Protocol HPC3001, it was previously required that female partners performed pregnancy tests regularly. An additional Skindex-16 questionnaire was added at the first unscheduled visit for rash management for subjects who presented with any rash. Comparison of treatments on severity and impact of rash in subjects who experienced rash was a secondary objective instead of an exploratory objective.
    25 May 2012
    In the second amendment CTPA-GEN-II,criterion related to the liver biopsy requirement (inclusion criterion 2) was updated and provided clarification about when and which alternative non-invasive methods were to be used. The definition of viral breakthrough and the on-treatment failure definition were clarified. Removal of erythropoiesis-stimulating agents from the list of disallowed medications to treat treatment-emergent anemia. Reduction in HCV RNA from baseline of <2 log10 IU/mL assessed after Week 12 until Week 24 was considered adequate for the identification of subjects with prior null response. The eligibility cut-off for alpha-fetoprotein (AFP) was increased from 50 to 100 ng/mL. A CT or MRI examination was mandatory for inclusion of cirrhotics with elevated AFP levels. Clarifications in the Pre study and Concomitant Therapy section, the Safety Evaluation section and the Study Medication Withdrawal section. Revision of the overall sampling schedule for pharmacokinetics evaluations following analysis of recent Phase 2 trials. Further recommendations were added related to female partners of male subjects who do not have to perform a pregnancy test because of privacy protection regulations. The Roche Cobas TaqMan HCV Test v2.0, for use with the High Pure System was used as the assay to determine HCV RNA levels. On request of Health Authorities, the key performance characteristics were added and the assay performance and validation documents were added to the reference list. The statistical methods were updated based on Health Authorities feedback regarding the primary endpoint, resulting in an update of the secondary endpoints. In addition, PROs were updated.

    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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