Table.

Challenges encountered in the implementation of a therapeutic trial for pediatric TBM, and resources and advancements needed to facilitate future research in this area

Challenges in conducting TBM trials	Requirements for optimal implementation
Tertiary hospital setting required, high screening-to-enrollment ratios, and large catchment areas	Substantial financial and human resources
TBM is rare in any one location	More resources for multisite recruitment
Diagnosis of TBM is hard to make and accrual is slow.	Advanced and rapid diagnostics with high sensitivity for confirming TBM  • Xpert Ultra, a test with higher sensitivity for detecting M. tuberculosis can be used—import approval into India has just been received  • Further work on CSF diagnostics and biomarkers may be useful  • Screening of all children with severe forms of TB to look for TBM may help identify TBM Low cost and child-friendly drug formulations with longer shelf life,
Anti-TB drug formulations are expensive, not readily available for pediatric populations, have shorter expiry periods and it is challenging to optimize the dose across weight bands	Low cost and child-friendly drug formulations with longer shelf life, allowing appropriate dosing across the different weight bands, is readily available and accessible  • Pediatric formulations, particularly stand-alone rifampin, would be useful for (commonly under-dosed) intrathoracic TB, as well as TBM in children  • The Global Drug Facility is now allowing investigators to purchase study drugs for clinical trials from their facility, reducing the amount of drug that should be purchased, by batching orders to the company
Training in assessing functional status and neurocognitive function is intensive and should be ongoing	Capacity building to develop or build upon existing expertise—neurology, neurocognitive and neuroradiological assessments—at international sites in areas where TB is common is key
It may be challenging to detect treatment response in a highly variable disease in children across the age continuum	Validated surrogate markers of treatment response for TBM in children so that we can discriminate efficiently among experimental therapies and identify those regimens that work best for neurologic, functional, and neurocognitive recovery. Longitudinal assessments of functional status or neurocognitive function may be useful in that regard, coupled with exposureresponse assessments
Children suffer comorbid conditions (hospital-acquired infections, seizures, nephrotic syndrome, malignancies, etc.) which should be managed, with attention to drug interactions, adverse event determination, and unintended anti-TB effects of concomitant medications	Laboratory capacity to perform drug-level monitoring, and for diagnosing alternative etiologies to aid the accurate assessment of the relationship of study and/or concomitant medications to the adverse events
Importantly, families and children suffer terribly from this disease, so extreme care is needed in explaining risks and benefits of study participation and in longitudinal care of these children and their caregivers over months-long treatment	Qualitative research to help us understand the sociodemographic, behavioral, and other barriers to trial participation and treatment adherence would aid in improving enrollment strategies and support structures