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Diagnosis of Tuberculosis in Swiss Children (CITRUS)

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ClinicalTrials.gov Identifier: NCT03044509
Recruitment Status : Recruiting
First Posted : February 7, 2017
Last Update Posted : December 11, 2020
Sponsor:
Collaborators:
Ospedale Regionale Bellinzona e Valli
University Hospital Inselspital, Berne
University of Lausanne Hospitals
University Hospital, Geneva
Luzerner Kantonsspital
Cantonal Hospital of St. Gallen
University Children's Hospital, Zurich
Kantonsspital Aarau
Information provided by (Responsible Party):
Dr. Nicole Ritz, MD/PhD, University Children's Hospital Basel

Brief Summary:
  1. The primary objective is to improve the sensitivity of novel immunodiagnostic tests for detection of TB disease in children.
  2. The secondary objective is to determine biomarkers that discriminate children with TB infection and disease.

Condition or disease Intervention/treatment
Tuberculosis Mycobacterium Tuberculosis Diagnostic Test: Secreted cytokine assay Diagnostic Test: Intracellular cytokine assay

Detailed Description:
  1. This will be done by measuring a variety of parameters in the blood samples and compare them with the current diagnostic gold standard for TB or for culture/NAAT non-confirmed TB cases a consensus case definition is used.

    Currently available immunodiagnostic tests (IGRA/TST) will be compared to novel immunodiagnostic tests which will include:

    • several novel, additional M. tuberculosis-specific Antigens
    • cytokines that are highly expressed
  2. Since there is no diagnostic gold standard for TB infection we will rely on a clinical composite reference standard for diagnosing TB infection. Biomarkers will be determined by:

    • including M. tuberculosis-specific antigens that are specifically expressed in either TB infection or disease,
    • measuring phenotypes and cytokine production of M. tuberculosis-specific cells.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 190 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 2 Months
Official Title: Evaluation and Validation of Novel Immunodiagnostic Tests for Childhood Tuberculosis Infection and Disease in Switzerland. The CITRUS (ChIldhood TubeRcUlosis in Switzerland) Study.
Actual Study Start Date : May 12, 2017
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Group/Cohort Intervention/treatment
TB exposure Diagnostic Test: Secreted cytokine assay
Blood collected in a sodium-heparin tube will be used for the assay using novel TB-specific antigens. After incubation the supernatant will be harvested and cryopreserved at -80 °C for further testing of cytokines. Cytokines will be measured using a bead-based multiplex assay reader (MAGPIX, Luminex Crop., Austin, USA).

Diagnostic Test: Intracellular cytokine assay
Blood will be stimulated with recombinant MTB-specific antigens, ESAT-6, CFP-10, positive control or left unstimulated. Following an initial duration of stimulation, Brefeldin-A will be added and the blood incubated for a further 5 hours. White cells will be fixed and cryopreserved at - 80°. Batched analysis within 6 months of cryopreservation will be done using multi-colour flow cytometry.

TB infection (latent TB) Diagnostic Test: Secreted cytokine assay
Blood collected in a sodium-heparin tube will be used for the assay using novel TB-specific antigens. After incubation the supernatant will be harvested and cryopreserved at -80 °C for further testing of cytokines. Cytokines will be measured using a bead-based multiplex assay reader (MAGPIX, Luminex Crop., Austin, USA).

Diagnostic Test: Intracellular cytokine assay
Blood will be stimulated with recombinant MTB-specific antigens, ESAT-6, CFP-10, positive control or left unstimulated. Following an initial duration of stimulation, Brefeldin-A will be added and the blood incubated for a further 5 hours. White cells will be fixed and cryopreserved at - 80°. Batched analysis within 6 months of cryopreservation will be done using multi-colour flow cytometry.

TB disease (active TB) Diagnostic Test: Secreted cytokine assay
Blood collected in a sodium-heparin tube will be used for the assay using novel TB-specific antigens. After incubation the supernatant will be harvested and cryopreserved at -80 °C for further testing of cytokines. Cytokines will be measured using a bead-based multiplex assay reader (MAGPIX, Luminex Crop., Austin, USA).

Diagnostic Test: Intracellular cytokine assay
Blood will be stimulated with recombinant MTB-specific antigens, ESAT-6, CFP-10, positive control or left unstimulated. Following an initial duration of stimulation, Brefeldin-A will be added and the blood incubated for a further 5 hours. White cells will be fixed and cryopreserved at - 80°. Batched analysis within 6 months of cryopreservation will be done using multi-colour flow cytometry.




Primary Outcome Measures :
  1. Improvement of immunodiagnostic tests for TB in children. [ Time Frame: 27 months ]
    Based on current evidence it is estimated that the sensitivity of the immunodiagnostic tests with regard to the identification of patients with TB infection or disease versus no TB is approximately 80 %. By applying a sample size approximation a minimum sample size of 126 patients with TB infection or disease (with a precision given by a 95 % confidence interval with a width of 20 %) will be needed to statistically show a significant result.


Secondary Outcome Measures :
  1. Indicative markers identification for TB infection and disease distinction [ Time Frame: 27 months ]
    A minimum sample size of 84 patients with TB infection is needed (with a precision given by a 95 % confidence interval with a width of 30 %). Among patients with TB infection or TB disease, a novel test is used to discriminate between these patient groups. It is estimated that the sensitivity of this test with regard to the identification of patients with TB infection (secondary outcome) is approximately 60 %.


Biospecimen Retention:   Samples Without DNA
For each child a total blood volume of 7.5 ml will be required for this study.


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
It will be a national multicentre study in Switzerland. Children will be recruited within SwissPedNet, the Swiss Research Network of Clinical Paediatric Hubs, which includes five University Children's Hospitals (Basel, Bern, Geneva, Lausanne and Zürich) and four cantonal A-clinics (Aarau, Bellinzona, Luzern and St. Gallen). Currently approximately 20-30 children with TB disease are notified in Switzerland each year. For TB infection in children there are no data available in Switzerland. However, data from the "Lungenliga Schweiz" show that in 2014, at least 232 children were examined for a TB contact investigation (correspondence with Jean-Pierre Zellweger and Jean-Marie Egger, Lungenliga Schweiz 13.08.2015). Of these 13 % (i.e. around 30 children) are categorized as TB infection per year.
Criteria

Inclusion Criteria:

  • all children / adolescents < 18 years of age undergoing evaluation for TB exposure, infection or disease.

Exclusion Criteria:

  • children / adolescents with TB infection or disease who have already been started on anti-mycobacterial treatment, children who have been treated for TB previously.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03044509


Contacts
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Contact: Nora Fritschi, Dr med +41617042947 nora.fritschi@ukbb.ch
Contact: Nicole Ritz, PD Dr med PhD +41617042947 nicole.ritz@ukbb.ch

Locations
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Switzerland
Kantonspital Aarau Recruiting
Aarau, Switzerland, 5001
Contact: Sara Bernhard-Stirnemann, Dr med    +41628384192    sara.bernhard@ksa.ch   
Nora Fritschi Recruiting
Basel, Switzerland, 4031
Contact: Nora Fritschi, Dr med    +41617042947    nora.fritschi@ukbb.ch   
Principal Investigator: Nicole Ritz, PD Dr med         
Sub-Investigator: Hanna Schmid, Dr med         
Sub-Investigator: Anja Jochmann, Dr med         
Sub-Investigator: Daniel Trachsel, PD Dr med         
Ospedale Regionale di Bellinzona Recruiting
Bellinzona, Switzerland, 6500
Contact: Lisa Kottanattu, Dr med    +41918118538    lisa.kottanattu@eoc.ch   
Inselspital Bern Recruiting
Bern, Switzerland, 3010
Contact: Andrea Duppenthaler, Dr. med.    +41316329414    andrea.duppenthaler@insel.ch   
Hôpital des enfants - HUG Recruiting
Genève, Switzerland, 1205
Contact: Anne Mornand, Dr. med.    +41223724579    anne.mornand@hcuge.ch   
Sub-Investigator: Marie Rohr, Dr. med.         
Kinserspital Luzern Recruiting
Luzern, Switzerland, 6016
Contact: Michael Buettcher, Dr med    +41412056657    michael.buettcher@luks.ch   
Kinderspital St Gallen Recruiting
St. Gallen, Switzerland, 9006
Contact: Jürg Barben, Prof Dr med    +41712437111    juerg.barben@kispisg.ch   
Sub-Investigator: Christian Kahlert, Dr med         
Kinderklinik Zürich Recruiting
Zürich, Switzerland, 8032
Contact: Christoph Berger, Prof Dr med    +41442667840    christoph.berger@kispi.uzh.ch   
Sub-Investigator: Christa Relly, Dr med         
Sponsors and Collaborators
University Children's Hospital Basel
Ospedale Regionale Bellinzona e Valli
University Hospital Inselspital, Berne
University of Lausanne Hospitals
University Hospital, Geneva
Luzerner Kantonsspital
Cantonal Hospital of St. Gallen
University Children's Hospital, Zurich
Kantonsspital Aarau
Investigators
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Principal Investigator: Nicole Ritz, PD Dr med UKBB
Additional Information:

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Responsible Party: Dr. Nicole Ritz, MD/PhD, PI, University Children's Hospital Basel
ClinicalTrials.gov Identifier: NCT03044509    
Other Study ID Numbers: CITRUS
First Posted: February 7, 2017    Key Record Dates
Last Update Posted: December 11, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Dr. Nicole Ritz, MD/PhD, University Children's Hospital Basel:
Immunodiagnostics tests
TB exposure
Latent TB
TB disease
Biomarkers
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections