A Trial in Subjects Suspected to Have Tuberculosis, Comparing the Diagnostic Performance of C-Tb to QuantiFERON®, in Combination With a Safety Assessment of C-Tb Versus Tuberculin PPD RT23 SSI

This study is currently recruiting participants.
Verified February 2014 by Statens Serum Institut
Sponsor:
Information provided by (Responsible Party):
Statens Serum Institut
ClinicalTrials.gov Identifier:
NCT01642888
First received: July 5, 2012
Last updated: February 18, 2014
Last verified: February 2014

July 5, 2012
February 18, 2014
September 2012
September 2014   (final data collection date for primary outcome measure)
  • To evaluate the diagnostic performance of C-Tb in relation to age, HIV and CD4 counts [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]
  • To evaluate the clinical safety of C-Tb, with emphasis on children and HIV positive participants [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: Yes ]
  • The sensitivity of C-Tb compared to that of QuantiFERON®- TB Gold In Tube test [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]

    The difference between sensitivity for C-Tb and for QuantiFERON® will be derived with a 95% confidence interval and a non-inferiority test will be performed by comparing the lower limit of the interval to a delta value of 0.15. This corresponds to testing the one-sided hypothesis H0: SensitivityC-Tb - SensitivityQF < -0.15 Against H1: SensitivityC-Tb - SensitivityQF > - 0.15

    at a 2.5% level. Rejecting the H0 corresponds to demonstrating non-inferiority of C-Tb versus QuantiFERON®.

  • The sensitivity of C-Tb compared to that of PPD [ Time Frame: From injections to 2-3 days after injections ] [ Designated as safety issue: No ]

    The endpoints sensitivity and specificity will be estimated non-linearly by finding the maximum likelihood estimates in a model describing the diagnostic outcome as a function of sensitivity, specificity and prevalence in different risk categories.

    This model will use all evaluable subjects with non-missing values for C-Tb and for PPD. Specificity will be compared as a superiority test while sensitivity will be compared with a non-inferiority limit of 0.15 as described above.

  • The specificity of C-Tb compared to that of QuantiFERON®- TB Gold In Tube test [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]

    The difference between sensitivity for C-Tb and for QuantiFERON® will be derived with a 95% confidence interval and a non-inferiority test will be performed by comparing the lower limit of the interval to a delta value of 0.15. This corresponds to testing the one-sided hypothesis H0: SensitivityC-Tb - SensitivityQF < -0.15 Against H1: SensitivityC-Tb - SensitivityQF > - 0.15

    at a 2.5% level. Rejecting the H0 corresponds to demonstrating non-inferiority of C-Tb versus QuantiFERON®. From the same model the specificity is estimated and a similar non-inferiority test is performed.

  • The specificity of C-Tb compared to that of PPD [ Time Frame: From injections to 2-3 days after injections ] [ Designated as safety issue: No ]
    This model will use all evaluable subjects with non-missing values for C-Tb and for PPD. Specificity will be compared as a superiority test while sensitivity will be compared with a non-inferiority limit of 0.15 as described above.
Complete list of historical versions of study NCT01642888 on ClinicalTrials.gov Archive Site
  • To evaluate the difference in sensitivity between C-Tb and QuantiFERON®-TB Gold in-Tube in trial participants with confirmed TB diagnosis, overall, and according to age and HIV status. [ Time Frame: From injections to 2-3 days after the injections ] [ Designated as safety issue: No ]
  • To evaluate the difference in sensitivity between C-Tb and Tuberculin PPD RT23 SSI in trial participants with confirmed TB diagnosis overall, and according to age and HIV status. [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]
  • To evaluate the difference in specificity between C-Tb and QuantiFERON®-TB Gold in-Tube 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. [ Time Frame: From injections to 2-3 days after the injections ] [ Designated as safety issue: No ]
  • To evaluate the difference in specificity between C-Tb and Tuberculin PPD RT23 SSI 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. [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]
  • To compare the diagnostic outcome of C-Tb to that of QuantiFERON®-TB Gold in-Tube using a latent class approach [ Time Frame: From injections to 2-3 days after the injections ] [ Designated as safety issue: No ]
  • To compare the diagnostic outcome of C-Tb to that of Tuberculin PPD RT23 SSI using a latent class approach [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]
  • To evaluate the diagnostic performance of Tuberculin PPD RT23 SSI in relation to age, HIV status and CD4 counts [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: No ]
  • To evaluate the clinical safety of Tuberculin PPD RT23 SSI [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: Yes ]
  • To evaluate the diagnostic performance of QuantiFERON®-TB Gold in-Tube in relation to age, HIV status and CD4 counts [ Time Frame: On the day of the injections ] [ Designated as safety issue: No ]
  • The diameter of induration at the C-Tb injection site measured transversely to the long axis of the forearm at 2 to 3 days after intradermal administration of C-Tb evaluated against the age and CD4 counts (HIV positive participants only) [ Time Frame: From injections to 2-3 days after the injections ] [ Designated as safety issue: No ]

    To evaluate a possible influence of age on the induration response, regression analyses will be performed separately for C-Tb and PPD. Response cut-offs will be used and only subjects with positive response will be included in the analyses. A linear, curvilinear or stepwise relationship will be used depending on the observed data. The SAP will state the final choice of cut-offs.

    A possible relationship between induration response and CD4 counts in the HIV positive sub-group will be evaluated as for the age above.

  • The diameter of induration at the PPD injection site measured transversely to the long axis of the forearm at 2 to 3 days after intradermal administration of PPD evaluated against the age and CD4 counts (HIV positive participants only) [ Time Frame: From injections to 2-3 days after the injections ] [ Designated as safety issue: No ]

    To evaluate a possible influence of age on the induration response, regression analyses will be performed separately for C-Tb and PPD. Response cut-offs will be used and only subjects with positive response will be included in the analyses. A linear, curvilinear or stepwise relationship will be used depending on the observed data. The SAP will state the final choice of cut-offs.

    A possible relationship between induration response and CD4 counts in the HIV positive sub-group will be evaluated as for the age above.

  • All adverse events occurring within 28 days after intradermal administration of C-Tb and PPD [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: Yes ]
    All adverse events occurring within 28 days after intradermal administration of C-Tb and Tuberculin PPD RT23 SSI will be tabulated descriptively.
  • Laboratory safety parameters: hematology, biochemistry and urinalysis in participants ≥ 5 years of age [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: Yes ]
    Laboratory safety parameters: hematology and biochemistry in participants ≥ 5 years of age will be tabulated descriptively and presented in shift tables.
  • Injection site adverse reactions within 2 to 3 days after intradermal administration of C-Tb and PPD [ Time Frame: Onset between the injections and 28 days after the injections ] [ Designated as safety issue: Yes ]
    The incidence of injection site adverse reactions within 2 to 3 days after intradermal administration will be compared between C-Tb and Tuberculin PPD RT23 SSI and the contrast will be presented with a confidence interval.
Not Provided
Not Provided
 
A Trial in Subjects Suspected to Have Tuberculosis, Comparing the Diagnostic Performance of C-Tb to QuantiFERON®, in Combination With a Safety Assessment of C-Tb Versus Tuberculin PPD RT23 SSI
A Phase III Trial in Subjects Suspected to Have Tuberculosis, 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 (PPD)

Tuberculosis (TB) continues to be one of the most serious bacterial infections worldwide and therefore new improved diagnostic tests are needed to help doctors in diagnosing TB.

The new skin test is named C-Tb. Like the current tuberculin skin test, PPD, the C-Tb test is injected just under the skin and will, when positive, show redness and/or swelling at the injection site while a negative test will leave no reactions. The investigators hope that this new C-Tb skin test will be more precise (specific) than the PPD test, as the PPD test e.g. may show a reaction if the person tested is BCG vaccinated.

The aim of this trial is to test the C-Tb skin test in volunteers suspected of having TB disease.

With focus on age, HIV status and CD4 count the following analyses are done (in an overall perspective):

  • To compare the C-Tb test to a blood test, the QuantiFERON test.
  • To compare the C-Tb test to the PPD test that is currently being used.
  • To assess the safety of the C-Tb test.

The TESEC-05 trial is an open comparison of the diagnostics performance of C-Tb compared to the QuantiFERON®-TB Gold In-Tube, in combination with a double-blind randomized split-body safety assessment of C-Tb versus to 2 T.U. Tuberculin PPD RT23 SSI.

The trial is a multi-centre Phase III clinical trial designed specifically to address C-Tb in relation to the paediatric population and to HIV infection. The intention is to evaluate how the C-Tb test performs in the paediatric population with respect to safety, and to ensure that SSI will be able to extrapolate data obtained in an adult population to the paediatric population.

Furthermore, the intention is both to evaluate the diagnostic performance and safety of C-Tb in HIV infected individuals and to evaluate whether SSI will be able to extrapolate data obtained in a non-HIV population to a HIV population.

The trial population will consist of paediatric participants with suspected TB infection and adult participants suspected to have TB disease. Furthermore a control group of 100 children between 5 - 11 years of age with no symptoms or known exposure will be recruited from an area with a "low" prevalence of TB (an area with an incidence rate < 299/100,000 per year, the average rate of TB in South Africa in 2005 was 645/100,000 per year.

The trial will be conducted in South Africa where the prevalence of HIV infection is high and MTb infections are endemic.

BCG vaccination at birth has been common practice since 1961 in South Africa. Thus most of the participants are presumed BCG vaccinated.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Tuberculosis
  • Biological: C-Tb
    The C-Tb agent is administered by the Mantoux injection technique to each volunteer in the RIGHT or LEFT forearm according to a double blind randomisation scheme
  • Biological: 2 T.U. Tuberculin PPD RT 23 SSI
    The 2 T.U. Tuberculin PPD RT 23 SSI agent is administered by the Mantoux injection technique to each volunteer in the RIGHT or LEFT forearm according to a double blind randomisation scheme
  • Experimental: 0.1 µg/0.1 mL C-Tb
    The C-Tb and 2 T.U. Tuberculin PPD RT 23 SSI agents are given concomitantly to each volunteer in the RIGHT and LEFT forearms according to a double blind randomisation scheme
    Intervention: Biological: C-Tb
  • Active Comparator: 2 T.U. Tuberculin PPD RT 23 SSI
    The C-Tb and 2 T.U. Tuberculin PPD RT 23 SSI agents are given concomitantly to each volunteer in the RIGHT and LEFT forearms according to a double blind randomisation scheme
    Intervention: Biological: 2 T.U. Tuberculin PPD RT 23 SSI
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1175
Not Provided
September 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

HIV NEGATIVE PARTICIPANTS:

  1. Participants between 5 and 65 years attending the TB clinic due to suspicion of TB disease
  2. Infants, toddlers and children between 28 days and 4 years must either have symptoms or signs of TB or be in close contact to a smear positive pulmonary TB case (more than 6 hours/day for at least five days)
  3. Is between 28 days and 65 years of age
  4. Participant, parent or legal guardian has signed the informed consent
  5. Is HIV negative confirmed by two rapid tests. However, children between 28 days and 4 years may have an unknown HIV status and may receive antiretroviral therapy (ART) or have breastfeeding mothers on ART
  6. Is willing and likely to comply with the trial procedures
  7. Is prepared to grant authorized persons access to their medical record

HIV POSITIVE PARTICIPANTS:

  1. Participants between 5 and 65 years attending the TB clinic due to suspicion of TB disease
  2. Infants, toddlers and children between 28 days and 4 years must either have symptoms* or signs** of TB or be in close contact to a smear positive pulmonary TB case (more than 6 hours/day for at least five days)
  3. Is between 28 days and 65 years of age
  4. Participant, parent or legal guardian has signed the informed consent
  5. Is HIV positive confirmed by:

    1. two positive rapid tests or
    2. 1 positive rapid test and an additional confirmatory ELISA test
  6. A CD4 count has been done
  7. Is willing and likely to comply with the trial procedures
  8. Is prepared to grant authorized persons access to their medical record

HIV NEGATIVE CONTROL GROUP:

  1. Participant with no known contact to people infected with MTb and no signs or symptoms of TB.
  2. Is between 5 and 11 years of age
  3. Participant, parent or legal guardian has signed the informed consent
  4. Is HIV negative confirmed by two rapid tests
  5. Is willing and likely to comply with the trial procedures
  6. Is prepared to grant authorized persons access to their medical record

Exclusion Criteria:

HIV NEGATIVE PARTICIPANTS:

  1. Has a confirmed diagnosis of tuberculosis at Screening Visit
  2. Has been vaccinated with a live vaccine within 6 weeks prior to the day of inclusion (e.g. MMR, yellow fever, oral typhoid vaccines) except BCG vaccine
  3. Has been tuberculin (TST) tested less than 12 months prior to the day of inclusion
  4. Is pregnant, breastfeeding or intending to get pregnant during the trial period
  5. Is a female of child bearing potential (12 years of age or older) not willing to use effective barrier (including spermicidal gel), hormonal or intrauterine contraceptive measures during the trial period
  6. Has an active disease affecting the lymphoid organs (e.g., Hodgkin's disease, lymphoma, leukaemia, sarcoidosis)
  7. Has a current skin condition which interferes with the reading of the C-Tb and PPD e.g. tattoos, severe scarring, burns/sunburns, rash, eczema, psoriasis, or any other skin disease at or near the injection sites
  8. Has a condition where blood drawings pose more than minimal risk for the participant, such as haemophilia, other coagulation disorders or significantly impaired venous access
  9. Currently participating in another clinical trial with an investigational or non-investigational drug or device or has participated in another clinical trial within the 3 months prior to dosing
  10. Has participated in previous clinical trials investigating the ESAT-6 and/or CFP-10 antigens
  11. Has a condition which in the opinion of the investigator is not suitable for participation in the trial

HIV POSITIVE PARTICIPANTS:

  1. Has a confirmed diagnosis of tuberculosis at Screening Visit
  2. Has been vaccinated with a live vaccine within 6 weeks prior to the day of inclusion (e.g. MMR, yellow fever, oral typhoid vaccines)
  3. Has been tuberculin (TST) tested less than 12 months prior to the day of inclusion
  4. Is pregnant, breastfeeding or intending to get pregnant during the trial period
  5. Is a female of child bearing potential (12 years of age or older) not willing to use effective barrier (including spermicidal gel), hormonal or intrauterine contraceptive measures during the trial period
  6. Has an active disease affecting the lymphoid organs except for HIV (e.g., Hodgkin's disease, lymphoma, leukaemia, sarcoidosis)
  7. Has a known diagnosis of AIDS or is receiving antiviral therapy at the time of Screening Visit
  8. Has a current skin condition which interferes with the reading of the C-Tb and PPD e.g. tattoos, severe scarring, burns/sunburns, rash, eczema, psoriasis, or any other skin disease at or near the injection sites
  9. Has a condition where blood drawings pose more than minimal risk for the participant, such as haemophilia, other coagulation disorders or significantly impaired venous access
  10. Currently participating in another clinical trial with an investigational or non-investigational drug or device or has participated in another clinical trial within the 3 months prior to dosing
  11. Has participated in previous clinical trials investigating the ESAT-6 and/or CFP-10 antigens
  12. Has a condition which in the opinion of the investigator is not suitable for participation in the trial

HIV NEGATIVE CONTROL GROUP:

  1. Has been vaccinated with a live vaccine within 6 weeks prior to the day of inclusion (e.g. MMR, yellow fever, oral typhoid vaccines) except BCG vaccine
  2. Has been tuberculin (TST) tested less than 12 months prior to the day of inclusion
  3. Has an active disease affecting the lymphoid organs (e.g., Hodgkin's disease, lymphoma, leukaemia, sarcoidosis)
  4. Has a current skin condition which interferes with the reading of the C-Tb and PPD e.g. tattoos, severe scarring, burns/sunburns, rash, eczema, psoriasis, or any other skin disease at or near the injection sites
  5. Has a condition where blood drawings pose more than minimal risk for the participant, such as haemophilia, other coagulation disorders, or significantly impaired venous access
  6. Currently participating in another clinical trial with an investigational or non-investigational drug or device, or has participated in another clinical trial within the 3 months prior to dosing
  7. Has participated in previous clinical trials investigating the ESAT-6 and/or CFP-10 antigens
  8. Has a condition which in the opinion of the investigator is not suitable for participation in the trial
Both
up to 65 Years
Yes
Contact: Bettine Borregaard, RN +45 3268 3416 BTG@ssi.dk
Contact: Erik Carp, M.Sc. +45 3268 8657 ECA@ssi.dk
South Africa
 
NCT01642888
TESEC-05, 2011-005078-40
Yes
Statens Serum Institut
Statens Serum Institut
Not Provided
Principal Investigator: Andreas Diacon, MD M2 Karl Bremer Hospital
Study Chair: Henrik Aggerbeck, M.Sc. Statens Serum Institut
Statens Serum Institut
February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP