Clinical trial NCT04240990: Development of a Diagnostic Prediction Score for Tuberculosis in Hospitalized Children With Severe Acute Malnutrition (TB-Speed SAM)
Official title: Development of a Diagnostic Prediction Score for Tuberculosis in Hospitalized Children With Severe Acute Malnutrition
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Tuberculosis
Severe Acute Malnutrition
Keywords: Tuberculosis
Child
Malnutrition
Diagnosis
Screening
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: UNITAID
First posted: 2020-01-27
Enrollment: 603
Sex: ALL
Minimum age (years): 2
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: TB-Speed SAM is a multicentric, prospective diagnostic cohort study assessing several diagnostic tests that could result in the development of a score and algorithm for TB treatment decision in hospitalised children with SAM.
Primary purpose: DIAGNOSTIC

Brief summary: TB-Speed SAM is a multicentric, prospective diagnostic cohort study conducted in two countries with high and very high TB incidence (Uganda and Zambia). It aims at assessing several diagnostic tests that could result in the development of a score and algorithm for TB treatment decision in hospitalised children with severe acute malnutrition (SAM).

Detailed description: There is now strong evidence that undiagnosed and untreated TB increases the risk of death in children, especially those severely malnourished who are highly vulnerable. Specific decision-making tools are therefore urgently needed to guide clinicians from high TB burden and low-income countries to initiate treatment quickly in children with SAM with suspected TB.

A diagnostic prediction score and algorithm was recently proposed by the investigators for TB treatment decision in HIV-infected children with presumptive TB (developed in the ANRS 12229 PAANTHER 01 study). Based on easily collected clinical features, chest X-Ray (CXR), Xpert MTB/RIF, and abdominal ultrasonography, the score aims to help clinicians make a same-day treatment decision. Such a prediction score improving TB diagnosis and shortening time to treatment initiation would be a key benefit in children with SAM.

Based on this experience, the investigators are proposing a diagnostic cohort study enrolling hospitalized severely malnourished children. The study will include the evaluation of several diagnostic tests that could be integrated in the development of a prediction model and subsequent score for the diagnosis of TB in hospitalized children with SAM. This will include Xpert MTB/RIF Ultra performed on one nasopharyngeal aspirate (NPA) and one stool sample, CXR, Quantiferon (QFT) Interferon-Gamma Release Assay (IGRA), Monocyte-to-lymphocyte ratio (MLR), and ultrasonography, which has shown its interest for the diagnosis of TB in both HIV-infected adults and children. In the PAANTHER study, it detected abdominal lymphadenopathy in 50% of culture confirmed TB cases and 35% of all confirmed and unconfirmed cases, with a specificity of 85%.

Using logistic regression, a score will be developed for TB diagnosis, considering confirmed and unconfirmed TB as reference diagnosis, in hospitalized children with SAM. As a secondary objective, and in order to reduce costs, sample collection, and complexity of the diagnostic process, a first-step screening score (excluding Ultra, abdominal ultrasound, and CXR if possible) will be developed to identify children with presumptive TB who would benefit from further diagnostic testing.

Both scores will be internally validated using resampling and will be incorporated in a stepwise algorithm to guide practical implementation of the screening and diagnosis process. The stepwise algorithm will be discussed with local clinicians involved in the study to better adapt it for future use in their routine practice.

The study will be implemented at inpatient nutrition centres from three selected tertiary hospitals in Uganda, and Zambia. A total of 720 children \<5 years old with WHO-defined severe acute malnutrition will be enrolled, that is approximately 240 participants per hospital.

Eligibility criteria: Inclusion Criteria:

* Children aged 2 to 59 months
* Severe acute malnutrition defined as weight-for-height Z score (WHZ) \< -3 standard deviation (SD) or mid-upper arm circumference (MUAC) \< 115 mm (in children over 6 months) or clinical signs of bilateral pitting oedema
* Hospitalized per hospital clinician's decision
* Parent/guardian informed consent

Exclusion Criteria:

- Ongoing TB treatment or history of intake of anti-TB drugs in the last 3 months

Primary outcomes:
measure: Sensitivity of the score obtained
timeFrame: 6 months
measure: Specificity of the score obtained
timeFrame: 6 months
Secondary outcomes:
measure: Prevalence of TB among hospitalized children with SAM
timeFrame: 6 months
measure: Clinical characteristics of TB disease in hospitalized children with SAM
timeFrame: 6 months
measure: Bacteriological characteristics of TB disease in hospitalized children with SAM
timeFrame: 6 months
measure: Biological characteristics of TB disease in hospitalized children with SAM
timeFrame: 6 months
measure: Radiological characteristics of TB disease in hospitalized children with SAM
timeFrame: 6 months
measure: Sensitivity of the score obtained
timeFrame: 6 months
measure: Specificity of the score obtained
timeFrame: 6 months
measure: Estimated time to TB treatment decision in hospitalized children with SAM
timeFrame: 6 months
measure: Diagnostic accuracy measures: 1/ Sensitivity of the different tests evaluated for the diagnosis of TB
timeFrame: 6 months
measure: Diagnostic accuracy measures: 2/ Specificity of the different tests evaluated for the diagnosis of TB
timeFrame: 6 months
measure: Diagnostic accuracy measures: 3/ Negative predictive value of the different tests evaluated for the diagnosis of TB
timeFrame: 6 months
measure: Diagnostic accuracy measures: 4/ Positive predictive value of the different tests evaluated for the diagnosis of TB
timeFrame: 6 months
measure: Diagnostic accuracy measures: 5/ AUROC of diagnostic prediction models with and without the different tests results
timeFrame: 6 months
measure: Diagnostic accuracy of Ultra performed on one NPA and one stool sample against a specific microbiological reference standard including Ultra and mycobacterial culture from gastric aspirates
timeFrame: 6 months
measure: Proportion of children with NPA and stool samples collected as per study protocol
timeFrame: 6 months
measure: Proportion of NPA-related adverse events (AEs)
timeFrame: 6 months
measure: Tolerability of NPA collection: 1/ Discomfort/pain/distress experienced by the child as assessed by the child
timeFrame: Within 3 days of inclusion
measure: Tolerability of NPA collection: 2/ Discomfort/pain/distress experienced by the child as assessed by the parents
timeFrame: Within 3 days of inclusion
measure: Tolerability of NPA collection: 3/ Discomfort/pain/distress experienced by the child as assessed by the nurse
timeFrame: Within 3 days of inclusion
measure: Mortality at 6 months
timeFrame: 6 months
measure: Percentage weight gain 6 months
timeFrame: 6 months
measure: TB treatment outcomes
timeFrame: 6 months
Other outcomes:
measure: Incremental cost-effectiveness ratio (ICER)
timeFrame: 32 months
Locations:
city: Kampala
country: Uganda
facility: Mulago National Referral Hospital
city: Lusaka
country: Zambia
facility: Lusaka University Teaching Hospital
city: Ndola
country: Zambia
facility: Arthur Davidson Children Hospital
Study officials:
affiliation: University of Bordeaux, France
name: Olivier Marcy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut de Recherche pour le Développemnt (IRD) Montpellier, France
name: Maryline Bonnet, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: MU-JHU Care Ltd, Kampala, Uganda
name: Eric Wobudeya, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: