A Multicentric Cohort and Biomarker Study for Improved Care of Patients with Extrapulmonary Tuberculosis
NCT ID: NCT06875336
Last Updated: 2025-03-13
Study Results
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Basic Information
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RECRUITING
150 participants
OBSERVATIONAL
2023-03-06
2025-12-31
Brief Summary
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Detailed Description
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Description:
Study population, research design and research methods Adult patients newly diagnosed with EPTB (N=150) will prospectively be enrolled into the study. PTB patients (N=30) will also be included and serve as a control group to test the technical feasibility. In addition, a healthy control group (N=30) will be added, mainly to address aim 1. Clinical data will be collected using standardized questionnaires over the whole treatment period for each individual.
Additionally, body fluids (blood, urine) will be collected and stored in a central biobank (Cologne). However, not all contributing centers will be able to provide high quality peripheral blood mononuclear cells (PBMCs) for storage. In order not to lose patients with incomplete sample collections, the cohort study will have several strata:
1. EPTB patients (N=100) with clinical data (e.g. weight gain, imaging results etc.) and a full collection of bio samples (routine laboratory parameters, peripheral blood mononuclear cells (PBMCs), PAXgene RNA/DNA tubes for gene signatures, absolute and relative CD4/CD8 cell count, Vitamin D (25(OH)D), urine, plasma)
2. EPTB patients (N=50) with clinical data (e.g. weight gain, imaging results, microbiology results etc.) plus/minus a partial collection of bio samples (e.g. routine laboratory results, Vitamin D (25(OH)D), PAXgene, plasma)
3. Healthy controls (N=30) and a full collection of bio samples as described for stratum 1 at one timepoint.
Data collection Pseudonymized clinical and laboratory data will be recorded at the following time points: diagnosis/ treatment initiation (day 0 / +/- 7 days); 4 weeks post treatment initiation (+/- 7 days); 3 months post treatment initiation (+/- 7 days); 6 months post treatment initiation (+/- 7 days); 3 months post end of treatment (+/- 7 days). In patients requiring treatment of more than 6 months (i.e. multi-drug resistant TB, disseminated TB etc.) data will be collected regularly until end of treatment. Pseudonymization of patient data and acquisition of biomaterial is performed through a patient ID-generator. A paper case report form (CRF) will be used to collect patient data. The CRF data will be then transferred to an electronic database.
Outcome:
Laboratory based biomarkers for assessing treatment responses similar to sputum conversion used for PTB are not available in most cases of EPTB. Unspecific inflammation markers such as C-reactive protein (CRP) can be utilized to assess early treatment response. We will systematically and longitudinally assess radiologic parameters (lesion size in CT, ultrasonography or MRI), laboratory findings and clinical signs (e.g. weight gain, less pain, absence of fever etc.). We will then exploit response algorithms specifically evaluated for EPTB patients initiating anti-TB treatment. A combination of three clinical parameters will be used 1) improvement in reported symptoms 2) weight gain (any weight gain or ≥ 5% weight gain) 3) regression of lymph node swelling, pleural or peritoneal effusion or other local findings, during and after treatment. A combination of these parameters predicts favorable or unfavorable outcome early during the treatment process.
Aims:
Our aim is to assess the treatment response using these parameters, supported by two independent clinicians and experts in the field (blind review). Data will be correlated with blood based biomarker findings described below. The main objectives of this study are the development of EPTB specific biomarkers for improved EPTB diagnostics and assessment of treatment responses by correlating immunological and blood based parameters and signatures with clinical features at baseline and longitudinally. For this purpose, our biomarker study will focus on two major aims:
Study aim I: Evaluation of blood biomarkers as diagnostic tools for EPTB Sputum or lung fluid based laboratory diagnostics as performed with PTB is not possible in most cases of EPTB. Blood based biomarkers are required.
* We will focus on two approaches: 1) blood derived gene expression signatures associated with tuberculosis; 2) T-cell based assays (e.g. TAM-TB assay).
* For this aim, we will first investigate markers that have already been analyzed in PTB patients. We will also be able to investigate EPTB specific markers in an unbiased fashion if necessary.
Study aim II: Evaluation of blood biomarkers predicting treatment response or failure and cure in EPTB
* Predicting cure or the risk of treatment failure is crucial for the management of EPTB. Various outcome definitions for PTB are based on culture and smear results which is not applicable in EPTB. Our aim is to correlate blood based biomarkers with the treatment response which we will assess with well-defined clinical parameters.
* For this aim we will continue with our evaluation of plasma IP-10 as a simple and cost-effective treatment response marker. Additional plasma-based markers have been described in our proposal. More complex markers/signatures (gene expression via RNA-seq and T-cell response based) will be applied using technical approaches similar to the ones exploited in Aim 1. We will primarily focus on signatures that have already been evaluated for PTB. The overarching goal of this unique multicenter cohort of patients with EPTB is the development.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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Patients with extrapulmonary tuberculosis
During the visits routine clinical and laboratory parameters (assessment of symptoms e.g. pain, weight gain, blood count, liver enzymes, renal parameters, vitamin D levels, CRP etc.), radiographic imaging (ultrasound, CT scan or MRI) and drug specific parameters (dose, interval, adverse events) are documented. Moreover, 3 sputum specimens (on 3 different days) and 1 urine specimen are collected initially for microscopy, PCR and culture through in-house microbiology departments.
A paper case record form (CRF) will be used to collect patient data, which will be then transferred to an electronic database by local study personnel.
At each time-point a series of additional specimens, consisting of serum, urine, heparin blood, and PAXgene blood for RNA will be collected and stored. If M. tuberculosis can be cultivated, strains will be stored for genotyping and whole genome sequencing. Serum biomarkers will be tested using commercially available kits.
biomarker analysis
PAXgene blood for RNA will be collected and stored. Results from these additional examinations are not included in the treatment monitoring of the patient concerned. If M. tuberculosis can be cultivated, strains will be stored for genotyping and whole genome sequencing. Serum biomarkers will be tested using commercially available kits.
In addition, TAM-TB assays will be performed from samples stored at each time-point. For this purpose, PBMCs will be collected and frozen using well-established protocols.
Interventions
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biomarker analysis
PAXgene blood for RNA will be collected and stored. Results from these additional examinations are not included in the treatment monitoring of the patient concerned. If M. tuberculosis can be cultivated, strains will be stored for genotyping and whole genome sequencing. Serum biomarkers will be tested using commercially available kits.
In addition, TAM-TB assays will be performed from samples stored at each time-point. For this purpose, PBMCs will be collected and frozen using well-established protocols.
Eligibility Criteria
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Inclusion Criteria
2. Isolation of Mycobacterium tuberculosis complex from a bodily secretion or tissue by
1. PCR
2. culture or a presumptive clinical diagnosis based on epidemiologic exposure in combination with physical findings, radiographic findings and/or histopathology
3. Patients with extrapulmonary TB
* pleura
* lymph nodes
* bones and joints
* larynx
* pericardial
* parotid gland
* abdominal sites
* kidneys
* genitourinary tract
* disseminated (miliary) TB
* other than pulmonary TB
4. In the case of pulmonary and extrapulmonary involvement, the leading manifestation, clinically and radiographically, must be extrapulmonary.
5. Written informed consent provided prior to inclusion
18 Years
ALL
No
Sponsors
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University Hospital, Bonn
OTHER
Research Center Borstel
OTHER
Johann Wolfgang Goethe University Hospital
OTHER
Universitätsklinikum Hamburg-Eppendorf
OTHER
University Hospital Heidelberg
OTHER
Helmholtz Zentrum München
INDUSTRY
University Hospital of Cologne
OTHER
University of Cologne
OTHER
Responsible Party
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Isabelle Suarez
Attending Physician
Locations
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University Hospital Bonn
Bonn, , Germany
Research Center Borstel
Borstel, , Germany
University Hospital of Cologne
Cologne, , Germany
University Hospital Frankfurt
Frankfurt, , Germany
University Hospital Hamburg
Hamburg, , Germany
University Hospital Heidelberg
Heidelberg, , Germany
Countries
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Central Contacts
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Facility Contacts
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References
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Fortun J, Martin-Davila P, Gomez-Mampaso E, Gonzalez-Garcia A, Barbolla I, Gomez-Garcia I, Wikman P, Ortiz J, Navas E, Cuartero C, Gijon D, Moreno S. Extra-pulmonary tuberculosis: differential aspects and role of 16S-rRNA in urine. Int J Tuberc Lung Dis. 2014 Apr;18(4):478-85. doi: 10.5588/ijtld.13.0555.
Gonzalez-Garcia A, Fortun J, Elorza Navas E, Martin-Davila P, Tato M, Gomez-Mampaso E, Moreno S. The changing epidemiology of tuberculosis in a Spanish tertiary hospital (1995-2013). Medicine (Baltimore). 2017 Jun;96(26):e7219. doi: 10.1097/MD.0000000000007219.
Grab J, Suarez I, van Gumpel E, Winter S, Schreiber F, Esser A, Holscher C, Fritsch M, Herb M, Schramm M, Wachsmuth L, Pallasch C, Pasparakis M, Kashkar H, Rybniker J. Corticosteroids inhibit Mycobacterium tuberculosis-induced necrotic host cell death by abrogating mitochondrial membrane permeability transition. Nat Commun. 2019 Feb 8;10(1):688. doi: 10.1038/s41467-019-08405-9.
Graham SM, Cuevas LE, Jean-Philippe P, Browning R, Casenghi M, Detjen AK, Gnanashanmugam D, Hesseling AC, Kampmann B, Mandalakas A, Marais BJ, Schito M, Spiegel HM, Starke JR, Worrell C, Zar HJ. Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update. Clin Infect Dis. 2015 Oct 15;61Suppl 3(Suppl 3):S179-87. doi: 10.1093/cid/civ581.
Mihret A, Bekele Y, Bobosha K, Kidd M, Aseffa A, Howe R, Walzl G. Plasma cytokines and chemokines differentiate between active disease and non-active tuberculosis infection. J Infect. 2013 Apr;66(4):357-65. doi: 10.1016/j.jinf.2012.11.005. Epub 2012 Nov 20.
Mulenga H, Zauchenberger CZ, Bunyasi EW, Mbandi SK, Mendelsohn SC, Kagina B, Penn-Nicholson A, Scriba TJ, Hatherill M. Performance of diagnostic and predictive host blood transcriptomic signatures for Tuberculosis disease: A systematic review and meta-analysis. PLoS One. 2020 Aug 21;15(8):e0237574. doi: 10.1371/journal.pone.0237574. eCollection 2020.
Odone A, Tillmann T, Sandgren A, Williams G, Rechel B, Ingleby D, Noori T, Mladovsky P, McKee M. Tuberculosis among migrant populations in the European Union and the European Economic Area. Eur J Public Health. 2015 Jun;25(3):506-12. doi: 10.1093/eurpub/cku208. Epub 2014 Dec 13.
Pai M, Nicol MP, Boehme CC. Tuberculosis Diagnostics: State of the Art and Future Directions. Microbiol Spectr. 2016 Oct;4(5). doi: 10.1128/microbiolspec.TBTB2-0019-2016.
Pang Y, An J, Shu W, Huo F, Chu N, Gao M, Qin S, Huang H, Chen X, Xu S. Epidemiology of Extrapulmonary Tuberculosis among Inpatients, China, 2008-2017. Emerg Infect Dis. 2019 Mar;25(3):457-464. doi: 10.3201/eid2503.180572.
Schaberg T, Bauer T, Brinkmann F, Diel R, Feiterna-Sperling C, Haas W, Hartmann P, Hauer B, Heyckendorf J, Lange C, Nienhaus A, Otto-Knapp R, Priwitzer M, Richter E, Rumetshofer R, Schenkel K, Schoch OD, Schonfeld N, Stahlmann R. [Tuberculosis Guideline for Adults - Guideline for Diagnosis and Treatment of Tuberculosis including LTBI Testing and Treatment of the German Central Committee (DZK) and the German Respiratory Society (DGP)]. Pneumologie. 2017 Jun;71(6):325-397. doi: 10.1055/s-0043-105954. Epub 2017 Jun 26. German.
Suarez I, Maria Funger S, Jung N, Lehmann C, Reimer RP, Mehrkens D, Bunte A, Plum G, Jaspers N, Schmidt M, Fatkenheuer G, Rybniker J. Severe disseminated tuberculosis in HIV-negative refugees. Lancet Infect Dis. 2019 Oct;19(10):e352-e359. doi: 10.1016/S1473-3099(19)30162-8. Epub 2019 Jun 7.
Paul G, Wesselmann J, Adzic D, Malin JJ, Suarez I, Priesner V, Kummerle T, Wyen C, Jung N, van Bremen K, Schlabe S, Wasmuth JC, Boesecke C, Fatkenheuer G, Rockstroh J, Schwarze-Zander C, Lehmann C. Predictors of serofast state after treatment for early syphilis in HIV-infected patients. HIV Med. 2021 Mar;22(3):165-171. doi: 10.1111/hiv.12985. Epub 2020 Oct 30.
Warnat-Herresthal S, Schultze H, Shastry KL, Manamohan S, Mukherjee S, Garg V, Sarveswara R, Handler K, Pickkers P, Aziz NA, Ktena S, Tran F, Bitzer M, Ossowski S, Casadei N, Herr C, Petersheim D, Behrends U, Kern F, Fehlmann T, Schommers P, Lehmann C, Augustin M, Rybniker J, Altmuller J, Mishra N, Bernardes JP, Kramer B, Bonaguro L, Schulte-Schrepping J, De Domenico E, Siever C, Kraut M, Desai M, Monnet B, Saridaki M, Siegel CM, Drews A, Nuesch-Germano M, Theis H, Heyckendorf J, Schreiber S, Kim-Hellmuth S; COVID-19 Aachen Study (COVAS); Nattermann J, Skowasch D, Kurth I, Keller A, Bals R, Nurnberg P, Riess O, Rosenstiel P, Netea MG, Theis F, Mukherjee S, Backes M, Aschenbrenner AC, Ulas T; Deutsche COVID-19 Omics Initiative (DeCOI); Breteler MMB, Giamarellos-Bourboulis EJ, Kox M, Becker M, Cheran S, Woodacre MS, Goh EL, Schultze JL. Swarm Learning for decentralized and confidential clinical machine learning. Nature. 2021 Jun;594(7862):265-270. doi: 10.1038/s41586-021-03583-3. Epub 2021 May 26.
Treatment of Tuberculosis: Guidelines. 4th edition. Geneva: World Health Organization; 2010. Available from http://www.ncbi.nlm.nih.gov/books/NBK138748/
WHO consolidated guidelines on tuberculosis: Module 4: Treatment - Drug-resistant tuberculosis treatment [Internet]. Geneva: World Health Organization; 2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK558570/
Chakaya J, Petersen E, Nantanda R, Mungai BN, Migliori GB, Amanullah F, Lungu P, Ntoumi F, Kumarasamy N, Maeurer M, Zumla A. The WHO Global Tuberculosis 2021 Report - not so good news and turning the tide back to End TB. Int J Infect Dis. 2022 Nov;124 Suppl 1:S26-S29. doi: 10.1016/j.ijid.2022.03.011. Epub 2022 Mar 20.
Chakaya J, Khan M, Ntoumi F, Aklillu E, Fatima R, Mwaba P, Kapata N, Mfinanga S, Hasnain SE, Katoto PDMC, Bulabula ANH, Sam-Agudu NA, Nachega JB, Tiberi S, McHugh TD, Abubakar I, Zumla A. Global Tuberculosis Report 2020 - Reflections on the Global TB burden, treatment and prevention efforts. Int J Infect Dis. 2021 Dec;113 Suppl 1(Suppl 1):S7-S12. doi: 10.1016/j.ijid.2021.02.107. Epub 2021 Mar 11.
Other Identifiers
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TTU 02.913_00
Identifier Type: -
Identifier Source: org_study_id
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