- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04203628
Evaluation of Four Stool Processing Methods Combined With Xpert MTB/RIF Ultra for Diagnosis of Intrathoracic Paediatric TB (TB-Speed - Stool Processing)
Evaluation of Four Stool Processing Methods Combined With Xpert MTB/RIF Ultra for Diagnosis of Intrathoracic Paediatric TB
Study Overview
Status
Conditions
Detailed Description
This is a diagnostic study evaluating the diagnostic accuracy of the Ultra assay in stools with a two-stage sequential design starting as a cohort of children with presumptive TB enriched in a second stage with Ultra positive TB cases on respiratory sample. It is both an ancillary to the TB-Speed HIV (C18-27) and the TB-Speed SAM (C18-28) studies and a study enrolling children from routine not enrolled in those two studies.
This design was chosen to be able to evaluate the sensitivity and specificity of the Ultra assay in a smaller sample size that is usually required by a "classical" prospective cohort design and avoiding the bias of overestimation of the sensitivity classically associated with the case-control design. In order to quickly generate data on appropriate stool processing method, and to contribute to the planned WHO recommendations for stool Ultra testing (expected 2nd semester 2020), a two-stage sequential design will be used. Indeed, knowing that on average only 10-15% of children with presumptive TB in a community-based setting will be confirmed, in order to reach the sample size of confirmed cases for the evaluation of sensitivity, 7 to 10 times more children with presumptive TB would need to be enrolled in a prospective design. On the other hand, the number of children with presumptive TB not confirmed with TB for the estimation of the specificity would be reached much earlier. In addition, based on the previous study results, it is known that the specificity of Xpert MTB/RIF assay in stool is high (99% CI:98-99;), which would result in a relatively small sample size to evaluate the specificity of the Ultra in stools.
During the first stage, the investigators will offer to join all consecutive presumptive TB cases presenting at study sites to estimate specificity with the expected precision and calculate a preliminary sensitivity estimate. During the second stage, the investigators will keep enrolling only those from TB Speed studies and routine care who are Xpert positive on respiratory samples in order to estimate sensitivity with the expected precision.
This two-stage sequential design first estimating specificity then sensitivity has been described by Wruck et al. as an efficient way of validating diagnostic tests when the prevalence of the disease is low. It would not be feasible to consecutively enrol all children with presumptive TB to describe an expected sensitivity of 60% with 10% precision as this would require over 900 patients, of which, approximately 800 would be culture negative. In the two-stage process described by Wruck, only reference standard positive samples from the original population are selected in stage 2. The investigators adapted this design to the TB context as culture results will only be available after enrollment (and if the child is positive, only after the child has started treatment), hence selecting only those who are Ultra positive on respiratory samples for the second cohort as a way of enriching the study population with a subpopulation that has a higher TB prevalence probability, before their true disease status is confirmed. Other comparable diagnostic studies have either used greater resources to include larger samples sizes or have resorted to reporting imprecise estimates of sensitivity. To our knowledge, this is a relatively unique approach to study design for accuracy studies, with few published examples.
With such design, there should be no bias on the evaluation of the specificity similarly to a classical prospective design because this evaluation will be done among consecutively enrolled children with presumptive TB only. The sensitivity estimates may not be generalizable to all culture confirmed TB children due to the sampling approach. Xpert positive children will be more likely to have higher biological loads, causing a possible inflation of the sensitivity. However, the results will provide valuable information on variations of sensitivities of the different stool processing methods within this population.
An interim analysis will be carried out after the completion of the prospective cohort in order to describe specificity and preliminary results of the sensitivity and the agreement between the processing methods. The recruitment of participants will not be put on hold during the interim analysis. A final analysis will be conducted at the end of the study to describe sensitivity as well as the secondary end points.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Manon Lounnas, PhD
- Phone Number: +33 (0)4 67 41 63 91
- Email: manon.lounnas@ird.fr
Study Contact Backup
- Name: Savine Chauvet, MSc
- Phone Number: +33 (0)4 67 41 64 89
- Email: savine.chauvet@ird.fr
Study Locations
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Mbarara, Uganda
- Recruiting
- Mbarara Regional Hospital
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Contact:
- Juliet MWANGA-AMUMPERE
- Email: Juliet.mwanga@epicentre.msf.org
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Lusaka, Zambia
- Recruiting
- Lusaka University Teaching Hospital
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Contact:
- Chishala CHABALA
- Email: cchabala@gmail.com
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Ndola, Zambia
- Recruiting
- Arthur Davidson Children Hospital
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Contact:
- Chishala CHABALA
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Contact:
- Email: cchabala@gmail.com
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria for the prospective cohort:
- Children < 15 years old
Presumptive intra-thoracic TB based on at least one criterion among the following:
- Persistent cough for more than 2 weeks
- Persistent fever for more than 2 weeks
- Recent failure to thrive (documented clear deviation from a previous growth trajectory in the last 3 months or Z score weight/age < 2)
- Failure of broad-spectrum antibiotics for treatment of pneumonia
- Suggestive CXR features
OR History of contact with a TB case and any of the symptoms listed under point 2 with shorter duration (< 2 weeks) if the child is HIV infected or presents with SAM.
- Signed informed consent by parent or guardian and assent signed by children > 7 years old
Inclusion Criteria for the enrichment cohort:
- Children < 15 years old
Presumptive intra-thoracic TB based on at least one criterion among the following:
- Persistent cough for more than 2 weeks
- Persistent fever for more than 2 weeks
- Recent failure to thrive (documented clear deviation from a previous growth trajectory in the last 3 months or Z score weight/age < 2)
- Failure of broad-spectrum antibiotics for treatment of pneumonia
- Suggestive CXR features
OR History of contact with a TB case and any of the symptoms listed under point 2 with shorter duration (< 2 weeks) if the child is HIV infected or presents with SAM.
- One positive Xpert (MTB/Rif or Ultra) result from at least on respiratory sample: sputum, NPA or GA
- Signed informed consent by parent or guardian and assent signed by children > 7 years old
Exclusion Criteria for prospective and enrichment cohorts:
- > 5 days of antituberculosis treatment in the last 3 months
- History of tuberculosis preventive therapy in the last 3 months
- Confirmed extrapulmonary TB only
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Prospective cohort
Any child with presumptive TB will be proposed to participate in the study. If the child is enrolled in the TB-Speed SAM or HIV studies, the study nurse will collect 2 stool samples then collect information about the clinical examination, chest X-ray, HIV-testing and the mycobacterial culture results as soon as they are available, from the data collected in the TB-speed records since all these procedures are already performed in these studies. For children identified from the routine practice, the nurse will collect 2 respiratory samples (sputum or GA) in consecutive children with presumptive TB to be tested using Ultra as done in routine care, record symptoms and refer the child for clinical exam and for chest X-ray. For the purpose of the study, 2 stool samples will be collected to be tested with Ultra. In addition, for study purpose the two respiratory samples will be tested with Mycobacterial culture as this test is not routinely prescribed for TB diagnosis in the study sites |
The Xpert MTB/Rif Ultra will be performed on stool samples processed using four different processing methods:
The Xpert MTB/Rif Ultra will be performed on gastric aspirate or expectorated sputum
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Experimental: Enrichment cohort
Any child with presumptive TB and a positive Xpert result from one respiratory sample (NPA, IS or GA) will be proposed to participate in the study. If the child is enrolled in the TB-Speed SAM or HIV studies, the study nurse will collect 2 stool samples then collect information about the clinical examination, chest X-ray, HIV-testing and the mycobacterial culture results as soon as they are available, from the data collected in the TB-speed records since all these procedures are already performed in these studies For children identified from the routine care, once enrolled, samples collected as routine practice will be tested with mycobacterial culture in addition to Xpert. If needed an additional respiratory sample will be collected (sputum or GA) and tested with Mycobacterial culture. The nurse will also record symptoms, refer the child for clinical exam and for chest Xray, and collect stool samples. HIV-testing will be offered for children with unknown HIV-status |
The Xpert MTB/Rif Ultra will be performed on stool samples processed using four different processing methods:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Sensitivity and sensibility of Ultra on stool
Time Frame: 8 weeks
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Sensitivity and specificity of Ultra on stool using TB culture reference standard (LJ and MGIT) in two respiratory samples (two sputums or two gastric aspirates according the age of the child).
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8 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Per-protocol analysis of diagnostic accuracy of Ultra on stool using TB culture reference standard
Time Frame: 8 weeks
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Per-protocol analysis of sensitivities and specificities of Ultra on stool using TB culture reference standard (LJ ans MGIT) in respiratory sample, excluding invalid Ultra results and contaminated culture results from analysis.
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8 weeks
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Sensitivities and specificities of each sampling method
Time Frame: 8 weeks
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8 weeks
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Proportion of Ultra "trace" results in stools out of the number of stools tested with Ultra
Time Frame: 8 weeks
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8 weeks
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Proportion of Ultra semi-quantitative results "very low"; "low"; "medium" and "high" in stool
Time Frame: 8 weeks
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8 weeks
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Proportion of invalid Ultra results from stool out of the number of stools tested with Ultra
Time Frame: 8 weeks
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8 weeks
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Proportion of Rifampicin resistant results on Ultra (stool and respiratory), LPA and DST
Time Frame: 8 weeks
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8 weeks
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Proportion of children successfully providing a stool sample
Time Frame: 8 weeks
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8 weeks
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Relative gain of the 2nd stool sample as compared to the 1st one
Time Frame: 8 weeks
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Relative gain of the 2nd stool sample as compared to the 1st one as measured by the number of additional positive results obtained from the addition of the 2nd sample as compared to the results of the first sample only
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8 weeks
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Feasibility assessment of the stool processing methods
Time Frame: 25 months
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Feasibility assessment by laboratory technician of their perception of ease of use, safety and suitability to low primary health care setting using a questionnaire and a standard "Ease of use score". The assessment will be divided into 2 parts:
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25 months
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Maryline Bonnet, MD, PhD, Institut de Recherche pour le Développement (IRD) Montpellier, France
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- C19-34
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
Data can be requested by members or partners of the TB-Speed consortium or by external research groups.
They can be used for secondary analyses of the TB-Speed project, country specific analyses, contribution to individual data meta-analysis and analyses that are not related to the research thematic of TB-Speed project.
The request for access to data will need to be sent to the Publication Committee accompanied by a concept paper describing the objectives of the analysis/study, how the data will be used, the list of data or material requested and how the original contributors will be credited.
Once the application is approved, data will be released under a data and/or material sharing agreement that secures the term of use.
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
- Informed Consent Form (ICF)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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