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
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Summary
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EudraCT number |
2011-005617-36 |
Trial protocol |
ES |
Global end of trial date |
02 Oct 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
29 May 2016
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First version publication date |
29 May 2016
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TESEC-06
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01631266 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Statens Serum Institut
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Sponsor organisation address |
Artillerivej 5, Copenhagen, Denmark, 2300
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Public contact |
Clinical Trials Department, Statens Serum Institut, +45 3268 3416, btg@ssi.dk
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Scientific contact |
Clinical Trials Department, Statens Serum Institut, +45 3268 3416, btg@ssi.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001156-PIP01-11 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Dec 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Oct 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Oct 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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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
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Jul 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 979
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Worldwide total number of subjects |
979
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EEA total number of subjects |
979
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
16
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Children (2-11 years) |
61
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Adolescents (12-17 years) |
44
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Adults (18-64 years) |
853
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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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 | ||||||||||||
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Pre-assignment
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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. | ||||||||||||
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Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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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.
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Arms
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Arm title
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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
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Investigational medicinal product code |
C-Tb
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Intradermal use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full Analysis Set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All subjects enrolled, randomised and tested irrespective of any results obtained
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End points reporting groups
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Reporting group title |
All subjects
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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
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All subjects enrolled, randomised and tested irrespective of any results obtained
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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
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End point type |
Primary
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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
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| 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 |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Binary response of C-Tb positivity across risk groups | ||||||||||||||||||||||||||||||
End point description |
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End point type |
Primary
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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)
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Statistical analysis title |
Logistic regression model | ||||||||||||||||||||||||||||||
Comparison groups |
All subjects v Full Analysis Set
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Number of subjects included in analysis |
1958
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||||||||||||||||||||
P-value |
≤ 0.05 | ||||||||||||||||||||||||||||||
Method |
Regression, Logistic | ||||||||||||||||||||||||||||||
Confidence interval |
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sides |
2-sided
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lower limit |
2.62 | ||||||||||||||||||||||||||||||
upper limit |
5.65 | ||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
1
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| 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. |
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Adverse events information
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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
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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)
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Assessment type |
Systematic | ||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
Safety set
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Reporting group description |
Threshold for non-serious adverse event reporting is: 5% | ||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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)
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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 |
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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 |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
