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    Clinical Trial Results:
    A phase IIa specificity trial of the diagnostic agent C-Tb, when given intradermally by the Mantoux technique to healthy volunteers previously vaccinated with BCG

    Summary
    EudraCT number
    2009-017296-17
    Trial protocol
    GB  
    Global end of trial date
    17 Oct 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Jul 2016
    First version publication date
    17 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TESEC-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Statens Serum Institut
    Sponsor organisation address
    Artillerivej 5, Copenhagen, Denmark, 2300
    Public contact
    Toxicology and Clinical Development Unit, Statens Serum Institut, kjmo@ssi.dk
    Scientific contact
    Toxicology and Clinical Development Unit, Statens Serum Institut, kjmo@ssi.dk
    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
    03 May 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the specificity of the C-Tb skin test as a function of the cut-off value (i.e., the smallest size of induration measured in mm resulting in a negative outcome of the C-Tb test) when the test is administered intradermally by the Mantoux technique to healthy BCG vaccinated adults. The present phase IIa (TESEC-03) trial in a healthy BCG vaccinated population collected data on the distribution of the induration response, if any, to C-Tb in this population. The specificity of the C-Tb test was defined as the relative frequency of subjects in a healthy population (i.e., no exposure to MTb) who have an induration response < cut-off after a C-Tb test.
    Protection of trial subjects
    Based on previous trials, 0.01 and 0.1 μg was considered safe and well tolerated.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 May 2011
    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
    United Kingdom: 151
    Worldwide total number of subjects
    151
    EEA total number of subjects
    151
    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)
    151
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This clinical trial was conducted at Surrey Clinical Research Centre, University of Surrey, Guildford, United Kingdom. First subject´s first visit: 09 May 2011 Last subject´s last visit: 17 October 2011

    Pre-assignment
    Screening details
    The screening visit (visit 1) took place up to 28 days before the inclusion visit (visit 2)

    Period 1
    Period 1 title
    Safety set (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    C-Tb and PPD RT 23 SSI were manufactured as solutions for injection and both appeared as clear and colourless liquids. Each subject was administered 1 injection of the IMP C-Tb (0.1 μg / 0.1 mL) in one arm and 1 injection of the comparator PPD RT 23 SSI (2 T.U. / 0.1 mL) in the other arm according to split body design using a randomisation code by the Mantoux injection technique, which is the currently approved injection technique for the comparator

    Arms
    Arm title
    All subjects
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    C-Tb + PPD RT 23 SSI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Each subject was administered 1 injection of the IMP C-Tb (0.1 μg / 0.1 mL) in one arm and 1 injection of the comparator PPD RT 23 SSI (2 T.U. / 0.1 mL) in the other arm according to a randomisation code by use of the Mantoux injection technique, which is the currently approved injection technique for the comparator. A disposable graduated 1 mL syringe equipped with a short-bevelled needle sized 26 gauges was used for the injection. Stretching the skin slightly and holding the needle almost parallel to the skin with the bevelled side upwards the needle was inserted through the epidermis into the flexor surface of the right or left volar part of the forearm 5-10 cm below the elbow point. The needle was visible through the epidermis before 0.1 mL of the test solution was injected slowly intradermally.

    Number of subjects in period 1
    All subjects
    Started
    151
    Completed
    149
    Not completed
    2
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Safety set
    Reporting group description
    -

    Reporting group values
    Safety set Total
    Number of subjects
    151 151
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    33.7 (18 to 65) -
    Gender categorical
    Units: Subjects
        Female
    92 92
        Male
    59 59
    Subject analysis sets

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol set consists of all subjects who have complied with the protocol and who have a non-missing diagnostic read out of C-Tb

    Subject analysis sets values
    Per protocol set
    Number of subjects
    147
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    34 (18 to 65)
    Gender categorical
    Units: Subjects
        Female
    89
        Male
    58

    End points

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    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    -

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol set consists of all subjects who have complied with the protocol and who have a non-missing diagnostic read out of C-Tb

    Primary: Specificity of C-Tb

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    End point title
    Specificity of C-Tb [1]
    End point description
    End point type
    Primary
    End point timeframe
    Days 2-3 after administration of C-Tb
    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: No parametric model for the distribution was proposed,so the empirical cumulative distribution function,defined on the range from 0mm to the maximal observed diameter will constitute the main outcome of the study. For each value of d (diameter of C-Tb) in this range, an exact 95% CI for the true value of F(d) will be calculated. The estimated value of F(d) can be interpreted as the specificity of a MTb test using the value d+1 as cut-off, i.e. values above d were considered MTb test positive
    End point values
    Per protocol set
    Number of subjects analysed
    147
    Units: percent
    number (confidence interval 95%)
        Diameter 0 mm
    97.3 (93.2 to 99.3)
        Diameter 5 mm
    99.3 (96.3 to 100)
        Diameter 6 mm
    99.3 (96.3 to 100)
        Diameter 10 mm
    100 (97.5 to 100)
        Diameter 15 mm
    100 (97.5 to 100)
    Attachments
    Untitled (Filename: Figure for T-03 EudraCT.docx)
    No statistical analyses for this end point

    Primary: Specificity of PPD

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    End point title
    Specificity of PPD [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 2-3 after administration of PPD RT 23 SSI
    Notes
    [2] - 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: No parametric model for the distribution is proposed,so the empirical cumulative distribution function,defined on the range from 0mm to the maximal observed diameter will constitute the main outcome of the study. For each value of d (diameter of PPD) in this range, an exact 95% CI for the true value of F(d) will be calculated. The estimated value of F(d) can be interpreted as the specificity of a MTb test using the value d+1 as cut-off, i.e. values above d are considered MTb test positive
    End point values
    Per protocol set
    Number of subjects analysed
    147
    Units: Percentage
    number (confidence interval 95%)
        Diameter 0 mm
    60.5 (52.2 to 68.5)
        Diameter 5 mm
    62.6 (54.2 to 70.4)
        Diameter 6 mm
    66 (57.7 to 73.6)
        Diameter 10 mm
    76.9 (69.2 to 83.4)
        Diameter 15 mm
    91.8 (86.2 to 95.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The duration of the safety follow-up period was 1. First hour after the administration of skin tests 2. 26-30 days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Safety set
    Reporting group description
    -

    Serious adverse events
    Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 151 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    97 / 151 (64.24%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    7 / 151 (4.64%)
         occurrences all number
    7
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    6 / 151 (3.97%)
         occurrences all number
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 151 (18.54%)
         occurrences all number
    33
    Dizziness
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Migraine
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    General disorders and administration site conditions
    Injection site haematoma
         subjects affected / exposed
    42 / 151 (27.81%)
         occurrences all number
    44
    Injection site pruritus
         subjects affected / exposed
    25 / 151 (16.56%)
         occurrences all number
    28
    Injection site pain
         subjects affected / exposed
    5 / 151 (3.31%)
         occurrences all number
    7
    Injection site rash
         subjects affected / exposed
    4 / 151 (2.65%)
         occurrences all number
    4
    Injection site discomfort
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Injection site erythema
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Injection site vesicles
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 151 (3.31%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    5 / 151 (3.31%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    5 / 151 (3.31%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 151 (1.99%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    3 / 151 (1.99%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 151 (10.60%)
         occurrences all number
    17
    Tonsillitis
         subjects affected / exposed
    2 / 151 (1.32%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2011
    Administrative changes, such as the outsourcing of the statistical reporting of the trial from Statens Serum Institut (SSI) to OnQ (CRO based in Johannesburg, SA)

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/23691171
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