Stool Processing Kit (SPK) Evaluation for Pediatric Tuberculosis (TB)

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multicenter cohort study in which the accuracy and the diagnostic yield of the Stool Processing Kit (SPK) in combination with Xpert Ultra MTB/RIF (Ultra) on stool samples will be assessed using a microbiological reference standard and a composite reference standard among children with signs and symptoms of pulmonary tuberculosis.

Detailed Description
-----------------
FIND and partners have developed a simple Stool Processing Kit (SPK) that will enable processing of large numbers of stool samples, removal of PCR (polymerase chain reaction) inhibitors which can be used at level 1 health facilities in low and middle income countries. The SPK is not a diagnostic kit as such but rather a sample processing method. This study aims to determine the sensitivity and specificity of Xpert Ultra MTB/RIF (Ultra) combined with SPK for TB detection using microbiological confirmation on respiratory specimens (defined as sputum, naso-pharyngeal aspirate, and/or gastric aspirate) as the reference standard. The investigators will further evaluate operational characteristics, including implementation considerations that will be needed for the potential rollout of the SPK. Additionally, a comparison of the performance of the SPK with up to two other centrifuge-free stool processing methods will be done on the same stool samples. The first is a method developed by researchers at the KNCV Tuberculosis Foundation (Single One Step Stool) which does not require any additional reagents other than the Ultra Sample Reagent. The second is a method developed by the Pediatric Asian African Network for Tuberculosis and HIV Research (PANTHER) group, the Optimized Sucrose Flotation method. Another diagnostic candidate, the urine Fujifilm SILVAMP TB LAM (FujiLAM) test will be assessed during the study. Therefore, if the sensitivity of any of these tests is shown to be promising this may support further research and provide other alternatives to respiratory samples.

Official Title
-----------------
Multicentre Study to Evaluate the Diagnostic Accuracy of a Stool Processing Kit Combined With Xpert MTB/RIF Ultra for Paediatric TB Diagnosis Using Microbiological Confirmation on Respiratory Samples as the Reference Standard

Conditions
-----------------
Tuberculosis

Intervention / Treatment
-----------------
* Device: Stool Processing Kit


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Children of 14 years of age or younger Written parent/guardian consent and child assent based on age and national ethical guidelines Willingness to have a study follow-up visit Clinical suspicion of active pulmonary TB* OR microbiological confirmation of active TB disease referred from non-study health facilities Chest X-ray suggestive of TB, or weight loss or failure to thrive within 3 months not solely due to inadequate feeding, or another non-TB cause, or any cough with loss of weight, or cough alone >=14 days, or persistent (>1 week) and unexplained fever Exclusion Criteria: Anti-TB treatment for >5 days or any antibiotic with anti-mycobacteria activity within 60 days prior to enrollment including children on Isoniazid Preventive Therapy (confirmed) extra-pulmonary TB only

Ages Eligible for Study
-----------------
Maximum Age: 14 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Intervention/Treatment |
| --- |
|Device: Stool Processing Kit|The Stool Processing Kit is a centrifuge-free stool processing solution that allows preparation of stool samples for testing with the Xpert Ultra MTB/RIF assay|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity and specificity of a single Ultra/SPK using microbiological confirmation on respiratory specimens as reference standard | Point estimates of sensitivity and specificity with 95% confidence intervals, using microbiological confirmation including two cultures and two Xpert MTB/RIF Ultra in respiratory samples | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic accuracy of a single Ultra/SPK using the National Institutes of Health (NIH) consensus definition as reference standard | Point estimates of sensitivity and specificity with 95% confidence intervals, using the Revised Classification NIH classification for diagnostic evaluation studies in children (Graham et al., CID 2015) | 2 months | 
| Diagnostic accuracy of a single Ultra/SPK for Rifampin resistance detection | Point estimates of sensitivity and specificity with 95% confidence intervals, with the Mycobacteria Growth Indicator Tube (MGIT) Drug Susceptibility Testing (DST) on respiratory specimens as reference standard | 2 months | 
| Additional yield (increase in sensitivity) of a 2nd Ultra/SPK | Sensitivity of a 2nd sampling on the same stool with Ultra/SPK for TB and RIF resistance detection using the different reference standards (Outcome 1 & 2) | 2 months | 
| Diagnostic accuracy of a single Ultra/SPK for TB detection per subgroup | Sensitivity and specificity of Ultra/SPK by sample, by site, by smear status, by HIV status, by TB history, by stool consistency, and by age using the different reference standards (Outcome 1 & 2) | 2 months | 
| Diagnostic accuracy of additional interventions: Simple One Step (SOS), Optimized Sucrose Flotation (OSF) and Fujifilm SILVAMP TB LAM | Sensitivity and specificity, by intervention using the different reference standards (Outcome 1 & 2) and by subgroup (Outcome 5) | 2 months | 
| Feasibility and user appraisal of the different stool processing methods | Assessment of user appraisal on ease of use and potential implementation of stool processing methods using a standardized questionnaire | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diagnostics, Children