E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Children (28 days–4 years old) with suspected Mycobacterium tuberculosis infection Participants between 5–65 years old who attended the TB clinic due to suspicion of TB disease (HIV positive and HIV negative) |
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E.1.1.1 | Medical condition in easily understood language |
If a participant had a suspected TB case and attended a TB clinic and both HIV positive and HIV negative participants were included |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1) To evaluate the diagnostic performance of C-Tb in relation to age, HIV status and CD4 counts: a) To evaluate C-Tb induration diameters as a function of age, with emphasis on children b) To evaluate C-Tb induration diameters as a function of HIV status c) To evaluate C-Tb induration diameters as a function of CD4 counts in HIV-positive participants d) To evaluate C-Tb positivity as a function of age, with emphasis on children using the above cut-off values to define positivity e) To evaluate C-Tb positivity according to HIV status using the above cut-off value to define positivity f) To evaluate C-Tb positivity according to CD4 counts in HIV-positive participants using the above cut-off values to define positivity
2) To evaluate the clinical safety of C-Tb with emphasis on children and HIV-positive participants |
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E.2.2 | Secondary objectives of the trial |
1) To evaluate the difference in sensitivity between C-Tb vs QFT and C-Tb vs PPD in trial participants with confirmed TB diagnosis overall, and according to age and HIV status 2) To evaluate the difference in specificity between C-Tb vs QFT and C-Tb vs PPD in the control group of 100 children aged 5–11 years with no TB symptoms and no known exposure to Mtb overall, and according to age 3) To compare the diagnostic outcome of C-Tb to that of QFT using a latent class approach 4) To compare the diagnostic outcome of C-Tb to that of PPD using a latent class approach 5) To evaluate the diagnostic performance of PPD RT 23 SSI in relation to age, HIV status and CD4 counts 6) To evaluate the clinical safety of PPD 7) To evaluate the diagnostic performance of QFT in relation to age, HIV status and CD4 counts |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The trial population consisted of 2 types of population: 1) Symptomatic or with relevant recent exposure: Children (28 days–4 years old) with suspected Mycobacterium tuberculosis infection, children and adults between 5–65 years old suspected to have TB disease and 2) children between 5–11 years old with no TB symptoms or known exposure to Mycobacterium tuberculosis recruited from an area with a ‘low’ prevalence of TB.
Age groups: • Paediatric: 28 days–23 months, 2–4, 5–11, 12–17 years • Adults: 18–39 and 40–65 years
Major inclusion criteria: • HIV-negative participants with suspicion of TB disease • HIV-positive participants with CD4 count performed and with suspicion of TB disease • HIV-negative children (5–11 years) with no symptoms of TB and no known contact with the Mycobacterium tuberculosis-infected case. This group was used as a negative (healthy) control. |
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E.4 | Principal exclusion criteria |
Major exclusion criteria (irrespective of HIV status): • Had confirmed diagnosis of TB at screening visit • Had been vaccinated within 6 weeks before day of inclusion • Had been tuberculin tested <12 months before day of inclusion • Was pregnant, breastfeeding or intended to get pregnant during the trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Diameter of induration at the C-Tb injection site measured transversely to the long axis of the forearm 2–3 days after intradermal administration of C-Tb • Positivity of each participant as evaluated by the C-Tb induration at day 2–3 using a predefined cut-off of 5 mm.
• All AEs occurring within 28 days after intradermal administration of C-Tb and PPD RT 23 SSI • Laboratory safety parameters: haematology and biochemistry in participant ≥5 years of age |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Diameter of induration at the PPD RT 23 SSI injection site measured transversely to the long axis of the forearm at 2–3 days after intradermal administration of PPD RT 23 SSI • Positivity of each participant as evaluated by the PPD RT 23 SSI induration at day 2–3 according to the pre-defined cut-off values of 5 and 15 mm that define positivity (see Section 8) • QFT raw test results in IU/ml • QFT dichotomised test result pre-defined by the standard cut-off values of 0.35 IU/mL |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At day 2–3 • All AEs occurring within 28 days after intradermal administration of C-Tb and PPD RT 23 SSI • Laboratory safety parameters: haematology and biochemistry in participant ≥5 years of age |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
All subjects were given C-Tb and PPD using split body randomised and blinded |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 25 |