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    Clinical Trial Results:
    A phase III contact tracing trial comparing the diagnostic performance of C-Tb to QuantiFERON®-TB Gold In-Tube, in combination with a double blind randomized split body safety assessment of C-Tb versus 2 T.U. Tuberculin PPD RT23 SSI

    Summary
    EudraCT number
    2011-005617-36
    Trial protocol
    ES  
    Global end of trial date
    02 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    29 May 2016
    First version publication date
    29 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TESEC-06
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01631266
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Statens Serum Institut
    Sponsor organisation address
    Artillerivej 5, Copenhagen, Denmark, 2300
    Public contact
    Clinical Trials Department, Statens Serum Institut, +45 3268 3416, btg@ssi.dk
    Scientific contact
    Clinical Trials Department, Statens Serum Institut, +45 3268 3416, btg@ssi.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001156-PIP01-11
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -To demonstrate an increasing trend in C-Tb positivity across the 4 risk (exposure) groups with positivity defined as an induration ≥ 5 mm
    Protection of trial subjects
    The dose-finding trial TESEC-02 in recently diagnosed TB patients concluded from a clinical perspective that injection of 0.1 µg/0.1 mL C-Tb was safe and resulted in an induration response similar to the response of PPD RT 23 SSI. Both TESEC-03 and TESEC-04 confirmed that the injection of 0.1 µg/0.1 mL of C-Tb was safe and well tolerated. It was therefore concluded that subjects injected with this dosage would be exposed to minimal risks in the present TESEC-06 trial, such as local reversible adverse reactions at the injection sites. The DSMB was established prior to the start of the trial and the members consisted of 3 independent medical doctors. The board had an advisory function and, if requested by the national PI, evaluated critical events in the trial to ensure the safety of all subjects. Safety reports were to be sent to the DSMB 2 times during the trial for evaluation: after 200 and after 500 subjects had completed the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Jul 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
    Spain: 979
    Worldwide total number of subjects
    979
    EEA total number of subjects
    979
    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)
    16
    Children (2-11 years)
    61
    Adolescents (12-17 years)
    44
    Adults (18-64 years)
    853
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Each of the 13 sites in Spain recruited subjects under the responsibility of a site investigator. First subject´s first visit: 24 July 2012 Last subject´s last visit: 02 October 2014

    Pre-assignment
    Screening details
    At visit1, screening visit (day -28–0). Informed consent was obtained and examinations were performed in order to determine if the subject fulfils the inclusion and exclusion criteria for the trial. A total of 993 patients were screened, of which 14 (1.4%) were screening failures.

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    This is a split-body double blind trial where the mode of injection of skin tests were randomised in split-body design where neither the investigator nor the subject knew which skin test was administered to each forearm. Thus this trial was not a blinded trial in a conventional sense as all subjects were given C-Tb and PPD RT 23 SSI (except 50 subjects in the Negative control group who received only a single injection of C-Tb) and there was no placebo.

    Arms
    Arm title
    All subjects
    Arm description
    The trial aimed to evaluate C-Tb’s positive response rates in 4 groups defined and ranked by ascending risk of Mtb infection to demonstrate a similar trend in positive responses to C-Tb: -Negative Control group: participants must have not had history of exposure to a TB index case and have no signs or symptoms of TB -Occasional Contact group: participants must have been in contact with a pulmonary TB index case (sputum or broncho smear positive, subsequently confirmed by Culture, GeneXpert or PCR) between 6 hours/week and 6 hours/day -Close Contact group: participants must have been in close contact with a pulmonary TB index case (sputum or broncho smear positive, subsequently confirmed by Culture, GeneXpert or PCR) for more than 6 hours/day for at least 5 days -Positive Control group: participants must have had TB disease within the last 3 years confirmed by culture, GeneXpert or PCR
    Arm type
    Experimental and Active comparator

    Investigational medicinal product name
    C-Tb
    Investigational medicinal product code
    C-Tb
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Concomitantly one injection of C-Tb (0.1 μg/0.1 mL) in one forearm and one injection of the PPD RT 23 SSI in the opposite forearm immediately one after each other according to the randomisation code. The Mantoux technique was employed for injection. A disposable graduated 1 mL syringe equipped with a short-bevelled needle sized 26 gauges was used for injection. According to this method, the skin was stretched slightly, and the needle held almost parallel to the skin with the bevelled side upwards. The needle was then inserted through the epidermis into the flexor surface of the right or left volar part of the forearm at a 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 and intradermally.

    Number of subjects in period 1
    All subjects
    Started
    979
    Completed
    970
    Not completed
    9
         Discontinued
    1
         Lost to follow-up
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Reporting group values
    overall trial Total
    Number of subjects
    979 979
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30.6 ± 14.5 -
    Gender categorical
    Units: Subjects
        Female
    524 524
        Male
    455 455
    BCG status
    Units: Subjects
        BCG vaccinated
    366 366
        BCG unvaccinated
    509 509
        BCG unknown
    104 104
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects enrolled, randomised and tested irrespective of any results obtained

    Subject analysis sets values
    Full Analysis Set
    Number of subjects
    979
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30.6 ± 14.5
    Gender categorical
    Units: Subjects
        Female
    524
        Male
    455
    BCG status
    Units: Subjects
        BCG vaccinated
    366
        BCG unvaccinated
    509
        BCG unknown
    104

    End points

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    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    The trial aimed to evaluate C-Tb’s positive response rates in 4 groups defined and ranked by ascending risk of Mtb infection to demonstrate a similar trend in positive responses to C-Tb: -Negative Control group: participants must have not had history of exposure to a TB index case and have no signs or symptoms of TB -Occasional Contact group: participants must have been in contact with a pulmonary TB index case (sputum or broncho smear positive, subsequently confirmed by Culture, GeneXpert or PCR) between 6 hours/week and 6 hours/day -Close Contact group: participants must have been in close contact with a pulmonary TB index case (sputum or broncho smear positive, subsequently confirmed by Culture, GeneXpert or PCR) for more than 6 hours/day for at least 5 days -Positive Control group: participants must have had TB disease within the last 3 years confirmed by culture, GeneXpert or PCR

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects enrolled, randomised and tested irrespective of any results obtained

    Primary: C-Tb positivity

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    End point title
    C-Tb positivity [1]
    End point description
    Number of subjects in each group: Negative control group = 263 Occasional contact group = 299 Close contact group = 316 Positive control group = 101
    End point type
    Primary
    End point timeframe
    The test positive subject was defined as an individual with an observation at day 2–3 (Visit 3) after the injection above the cut-off value of: • C-Tb: induration diameter ≥ 5 mm
    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: Test positivity rates for C-Tb were tabulated descriptively in total and split into risk groups. No statistical analysis was performed
    End point values
    All subjects
    Number of subjects analysed
    979
    Units: Subjects with positive C-Tb results
        Negative control group
    9
        Occasional contact group
    49
        Close contact group
    136
        Positive control group
    68
        Overall
    262
    No statistical analyses for this end point

    Primary: Binary response of C-Tb positivity across risk groups

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    End point title
    Binary response of C-Tb positivity across risk groups
    End point description
    End point type
    Primary
    End point timeframe
    The test positivity rate was defined as the prevalence of test positives, in a given subgroup of the trial population of interest at the time of test reading (Visit 3, 2–3 days after the injection)
    End point values
    All subjects Full Analysis Set
    Number of subjects analysed
    979
    979
    Units: Odds ratio
    number (confidence interval 95%)
        Positive – Negative
    47.603 (21.222 to 106.78)
    47.603 (21.222 to 106.78)
        Close – Negative
    17.852 (8.713 to 36.579)
    17.852 (8.713 to 36.579)
        Occasional – Negative
    4.643 (2.205 to 9.778)
    4.643 (2.205 to 9.778)
        Positive – Occasional
    10.253 (6.045 to 17.391)
    10.253 (6.045 to 17.391)
        Close – Occasional
    3.845 (2.617 to 5.65)
    3.845 (2.617 to 5.65)
        Positive – Close
    2.666 (1.646 to 4.319)
    2.666 (1.646 to 4.319)
    Statistical analysis title
    Logistic regression model
    Comparison groups
    All subjects v Full Analysis Set
    Number of subjects included in analysis
    1958
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    ≤ 0.05
    Method
    Regression, Logistic
    Confidence interval
         sides
    2-sided
         lower limit
    2.62
         upper limit
    5.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [2] - Purpose of analysis is to demonstrate a rising trend in C-Tb test positivity across 4 predefined risk groups of subjects . The contrast between close and occasional contact groups is selected as the most central below.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (both systemic AEs and injection site reactions) were collected and assessed at Visit 2, Visit 3 and Visit 4. Reporting of SAEs was in accordance with the defined procedure in trial protocol
    Adverse event reporting additional description
    This is a split-body double blind trial where C-Tb and PPD RT 23 SSI were each injected as per the randomisation scheme into each forearm. All subjects were given C-Tb and PPD RT 23 SSI (except 50 subjects in the Negative control group who received only single injection of C-Tb)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Safety set
    Reporting group description
    Threshold for non-serious adverse event reporting is: 5%

    Serious adverse events
    Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 979 (0.10%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Aspartate transferase increased
    Additional description: AST increased - Increased AST, more than 9.7 times normal upper limit Secondary SAEs in this subject were: Bilirubin increased ALT increased Alkaline phosphatase increased Platelets decreased
         subjects affected / exposed
    1 / 979 (0.10%)
         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
    Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    396 / 979 (40.45%)
    General disorders and administration site conditions
    Injection site reactions
    Additional description: Overall, 565 Injection site reactions in 341 (34.8%) subjects were reported.
         subjects affected / exposed
    318 / 979 (32.48%)
         occurrences all number
    484
    Systemic adverse events
    Additional description: Overall, 550 systemic AEs in 317 (32.4%) subjects were reported
         subjects affected / exposed
    137 / 979 (13.99%)
         occurrences all number
    171

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2012
    Added the word ‘double’ to indicate that double reading of the induration at V3 (day 2–3) and V4 (day 28±2) to be performed. The word ‘double’ reading was added throughout the protocol where relevant. Deleted ‘sputum smear microscopy’ activity from V1 (day -28–0) as the test was not needed A single cut-off for PPD of ≥ 6 mm was to be used according to the subject information leaflet for PPD Cut-off for C-Tb was to be calculated from the specificity trial (TESEC-03) and sensitivity trial (TESEC-04)
    24 Aug 2012
    Secondary objectives changed A new group of 50 subjects was added to the Negative Control group. This group was to be tested with C-Tb alone. Index cases to be enrolled in the Occasional and Close Contact groups should have positive sputum smear and either positive culture, GeneXpert or PCR Subjects to be enrolled in the Positive Control group could have a negative sputum smear but must have positive culture or GeneXpert At least 80 paediatric subjects should be enrolled, stratified by 4 age groups. Double reading of the induration should be independently performed by 2 staff members Double reading should be recorded in the source notes together with a consensus diameter. Only consensus diameter was to be recorded in the CRF Only the first 550 subjects would have safety blood samples taken Of the 120 paediatric subjects, at least 80 of them must be enrolled in the Occasional and Close Contact groups and divided by the 4 age groups: • 6 weeks–23 months: 20 subjects • 2–4 years: 20 subjects • 5–11 years: 20 subjects • 12–17 years: 20 subjects
    10 Dec 2012
    Primary objectives and endpoints changed Secondary objectives and endpoints changed Index cases in the Occasional and Close Contact groups must have either a positive sputum smear or broncho smear Changes in the SAP

    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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