- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04121026
Validation of a Tuberculosis Treatment Decision Algorithm in HIV-infected Children (TB-Speed HIV)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The ANRS 12229 PAANTHER 01 (Pediatric Asian African Network for Tuberculosis and HIV Research) study, which enrolled 438 HIV-infected children of median age 7.3 (IQR: 3.3 - 9.7) years with presumptive TB in four countries (Burkina Faso, Cameroon, Cambodia, Vietnam) from 2011 to 2014, aimed at developing a diagnostic prediction score and algorithm for TB treatment decision in HIV-infected children. This was the first study developing a TB diagnostic score exclusively in HIV-infected children, using methods recommended for diagnostic prediction models. Based on microbiological, clinical and radiological features, the best scoring system obtained had a sensitivity of 88.6% and specificity of 61.2% when Xpert MTB/RIF was included in the algorithm. The investigators showed previously that mortality is high in children with both confirmed and unconfirmed TB and that initiation of anti-TB treatment, that occurred at a median time of 7 (IQR: 5 - 11) days in the study, led to delayed ART initiation, which is associated to significantly increased mortality. The score, based on easily collected clinical features, chest radiographic features, Xpert MTB/RIF results, and abdominal ultrasonography, could enable same-day TB treatment decision. Abdominal ultrasonography has shown promise 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%.
Developed in tertiary research-experienced health facilities, the PAANTHER score could enable standardized treatment decision in HIV-infected children with presumptive TB, and could be recommended for extensive use in secondary and primary healthcare settings where most of these children are seeking care. However, external validation studies are now needed to assess the predictive performance of the PAANTHER diagnostic score on independent datasets.
The PAANTHER TB treatment decision algorithm will be used for a TB treatment decision by site clinicians in all children enrolled in the study. Validation of the algorithm will be performed by evaluating the safety of withholding TB treatment in children not initiated on treatment as per the PAANTHER TB treatment decision algorithm. The safety of this strategy will be carefully assessed through review of safety reports every 4 to 6 months during study conduct by the safety sub-committee of the SAB.
Occurrence of algorithm failures in terms of missed TB cases (TB cases subsequently detected among untreated cases, i.e. false negatives) and cases with unlikely TB among those initiated on TB treatment as per the algorithm (cases not secondarily validated as confirmed or unconfirmed TB cases by the expert committee, i.e. false positives) will enable to estimate the negative and positive predictive values of the algorithm.
A centralized international Expert Committee will clinically review and validate TB diagnosis in children. This will enable assessment of the added value of new markers (MLR and CRP) and, if need be, to propose a new version of the score based on an optimised predicted probability.
The TB-Speed HIV study will be implemented in 7 tertiary healthcare level hospitals in capital cities of Côte d'Ivoire, Uganda, Mozambique, and Zambia. A total of 550 HIV-infected children (aged < 15 years) with clinically suspected TB (presumptive TB) will be enrolled, using standard entry criteria. The inclusion period will last until all sites have reached the expected number of children enrolled.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Julien Poublan, MPH
- Email: julien.poublan@u-bordeaux.fr
Study Locations
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Abidjan, Côte D'Ivoire
- Recruiting
- Cocody University Teaching Hospital
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Contact:
- Country Principal Investigator
- Email: raoul.moh@pacci.ci
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Contact:
- Country co-Principal Investigator
- Email: koflaur@hotmail.com
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Abidjan, Côte D'Ivoire
- Recruiting
- Treichville University Teaching Hospital
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Contact:
- Country Principal Investigator
- Email: raoul.moh@pacci.ci
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Contact:
- Country co-Principal Investigator
- Email: koflaur@hotmail.com
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Maputo, Mozambique
- Recruiting
- José Macamo General Hospital
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Contact:
- Country Principal Investigator
- Email: khosacelso@gmail.com
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Contact:
- Country co-Principal Investigator
- Email: emacassa@gmail.com
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Maputo, Mozambique
- Recruiting
- Maputo Central Hospital
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Contact:
- Country Principal Investigator
- Email: khosacelso@gmail.com
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Contact:
- Country co-Principal Investigator
- Email: emacassa@gmail.com
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Mbarara, Uganda
- Recruiting
- Mbarara Regional Hospital
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Contact:
- Country Principal Investigator
- Email: Juliet.MWANGA@epicentre.msf.org
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Lusaka, Zambia
- Recruiting
- Lusaka University Teaching Hospital
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Ndola, Zambia
- Recruiting
- Arthur Davidson Children Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Children aged 1 month to 14 years
- Documented HIV-infection (i.e., confirmed before entry into the study)
Presumptive TB based on at least one criteria 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 3 with a shorter duration (< 2 weeks)
- Informed consent signed by parent/guardian
Exclusion Criteria:
Ongoing TB treatment or history of intake of anti-TB drugs in the last 3 months (isoniazid alone or rifampin/isoniazid for preventive therapy is not an exclusion criteria)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Diagnostic
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Proportion of missed TB cases
Time Frame: 6 months
|
Proportion of missed TB cases (false negative cases) in children not initiated on treatment as per the PAANTHER TB treatment decision algorithm
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Feasibility of the PAANTHER TB treatment decision algorithm (a): Proportion of children with presumptive TB having completed the algorithm.
Time Frame: 6 months
|
The algorithm will be considered completed if a decision to initiate TB treatment has been taken at any step of the algorithm or if TB has been excluded after systematic evaluation, and all steps planned in the algorithm have been implemented.
|
6 months
|
Feasibility of the PAANTHER TB treatment decision algorithm (b): Time to final TB treatment decision
Time Frame: 6 months
|
6 months
|
|
Proportion of HIV-infected children with unlikely TB among those initiated on treatment as per the PAANTHER TB treatment decision algorithm
Time Frame: 6 months
|
Proportion of cases considered as unlikely TB by the Expert Committee in those initiated on treatment as per the PAANTHER TB treatment decision algorithm (false positive)
|
6 months
|
Incidence of morbidity
Time Frame: 6 months
|
Incidence of morbidity defined as drug-induced toxicity (ART and TB treatment-related), opportunistic infections, and IRIS - with or without TB treatment
|
6 months
|
Incidence of mortality
Time Frame: 6 months
|
6 months
|
|
Time to ART initiation in ART-naïve children
Time Frame: 6 months
|
6 months
|
|
CD4 (absolute count and %) gain
Time Frame: 6 months
|
Immunologic evolution at 6 months after enrolment defined as CD4 cells gain (absolute count and %)
|
6 months
|
TB treatment outcomes (a): Weight gain at 6 months (absolute value and percentage of body weight)
Time Frame: 6 months
|
TB treatment outcome in HIV-infected children initiated on treatment as per the PAANTHER TB treatment decision algorithm defined by weight gain at 6 months (absolute value and percentage of body weight)
|
6 months
|
TB treatment outcomes (b): TB symptoms resolution in children on TB treatment
Time Frame: 6 months
|
6 months
|
|
Feasibility of IPT initiation (a): Time to IPT initiation
Time Frame: 6 months
|
Time to Isoniazid Preventive Therapy (IPT) initiation in HIV-infected children not initiated on treatment as per the PAANTHER TB treatment decision algorithm (a)
|
6 months
|
Feasibility of IPT initiation (b): Proportion of children initiated on IPT
Time Frame: 6 months
|
Proportion of children initiated on IPT in HIV-infected children not initiated on treatment as per the PAANTHER TB treatment decision algorithm (b)
|
6 months
|
Performance of the Monocyte-to-Lymphocyte Ratio and the C-reactive protein and their potential added value in the PAANTHER score and algorithm to detect TB
Time Frame: 6 months
|
Discrimination (area under the receiver-operating-characteristic curves [AUROC]) and calibration measures of the PAANTHER prediction model including or not MLR and CRP, against the TB composite reference standard as defined by the Expert Committee
|
6 months
|
Proportion of NPAs (or sputum) and stool samples with mycobacterium tuberculosis (MTB) detected using Ultra
Time Frame: 6 months
|
Diagnostic performance of Ultra performed on one NPA and one stool sample against mycobacterial culture performed on standard samples in HIV-infected children
|
6 months
|
Proportion of children with NPA and stool samples collected as per study protocol
Time Frame: 6 months
|
Feasibility of NPA and stool samples collection in HIV-infected children defined as the proportion of children with NPA and stool samples collected as per study protocol
|
6 months
|
Proportion of NPA-related adverse events (AEs)
Time Frame: 6 months
|
Safety of NPA collection defined as proportion of AEs (vomiting, nose bleeding, low oxygen saturation, respiratory distress) occurring during NPA
|
6 months
|
Discomfort/pain/distress experienced by the child during NPA as assessed by the child
Time Frame: Within 3 days of inclusion
|
Tolerability of NPA collection defined as discomfort/pain/distress experienced by the child during NPA, as assessed by the child using the Wong-Baker face scale (in a subset of children). Scale range: 0 (no hurt) - 5 (hurts worst) |
Within 3 days of inclusion
|
Discomfort/pain/distress experienced by the child during NPA as assessed by the parents
Time Frame: Within 3 days of inclusion
|
Tolerability of NPA collection defined as discomfort/pain/distress experienced by the child during NPA, as assessed by the parents using the visual analog scale (in a subset of children). Scale range: 0 (no pain) - 10 (pain as bad as it could possibly be) |
Within 3 days of inclusion
|
Discomfort/pain/distress experienced by the child during NPA as assessed by the nurse
Time Frame: Within 3 days of inclusion
|
Tolerability of NPA collection defined as discomfort/pain/distress experienced by the child during NPA, as assessed by the nurses using the "Face Legs Activity Cry Consolability" behavioral pain scale (in a subset of children). Total score range: 0 (relaxed and comfortable) - 10 (severe discomfort/pain). Each item of the FLACC scale - Face, Legs, Activity, Cry, Consolability - has 3 possible quotes: 0 or 1 or 2, with a precise description provided to help with the rating. The total score is obtained by adding individual item scores. |
Within 3 days of inclusion
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incremental cost-effectiveness ratio (ICER)
Time Frame: 33 months
|
Incremental cost-effectiveness ratio (ICER)
|
33 months
|
Collaborators and Investigators
Collaborators
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
- C18-27
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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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