Challenges in conducting trials for pediatric tuberculous meningitis: lessons from the field

Abstract

SETTING: TBM-KIDS is a phase I/II trial enrolling children with tuberculous meningitis (TBM) in three tertiary referral centers in India and Malawi.OBJECTIVE: To describe the challenges encountered in conducting the first randomized clinical trial of antimicrobial agents in pediatric TBM.DESIGN: The sources of the data were primarily monthly trial reports, non-enrollment case report forms, study diaries and registers maintained for recruitment, experiences shared by key team members during regular study calls and comments from site review visits. We reviewed, broadly categorized, and describe in detail the challenges encountered by study teams in trial implementation.RESULTS: Over 17 months, 3371 children with clinical presentations consistent with meningoencephalitis or undergoing lumbar puncture were assessed for eligibility; 21 (<1%) met enrollment criteria. We encountered challenges related to diagnosis, management of sick children, large catchment areas, adverse event attribution, concomitant medications, infrastructure requirements, expensive pediatric formulations with short expiry, and detection of treatment response in a highly variable disease across the age continuum. Training and adaptation of tools for neurocognitive and neurologic function assessment were necessary. Special care was undertaken to explain study participation to distraught caregivers and manage children longitudinally.CONCLUSION: Interventional trials in pediatric TBM are challenging but are critically important for improving the treatment of a disease that disables children physically, cognitively and emotionally. Sharing these challenges may help to address them more effectively as a TB research community and to advance treatments for this at-risk population.

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

“…Reasons for low enrollment have been described in detail previously [ 25 ] ( Figure 1 ). Children presenting with neurologic complaints, fever, or other indication for LP were numerous, with a broad range of diagnoses and reasons for prescreening failure ( Figure 1 ) [ 26 ]. The most common cause for screening failure was TBM diagnostic score <12.…”

“…In TBM-KIDS, outcomes were excellent, with rates of mortality and functional disability very low, across treatment arms. To participate in a TBM trial, a child must survive long enough to undergo diagnostic testing and treatment initiation, have parents who live in the trial site catchment area and agree for their critically ill child to participate, speak a language provided on a consent form, and meet laboratory inclusion criteria [ 26 ]. Children cannot have been on treatment for more than a few days before joining a therapeutic trial, so children doing poorly on treatment initiated at outside centers cannot join.…”

Comparative Effectiveness of Regimens for Drug-Susceptible Tuberculous Meningitis in Children and Adolescents: A Systematic Review and Aggregate-Level Data Meta-Analysis

“…Currently, 2 clinical trials of pediatric TB meningitis regimens are underway [ 6 , 25 ]. Although these interventional studies are important, they are challenging to carry out and subject to their own limitations; for instance, stricter enrollment criteria lead to highly selective participant populations [ 26 ].…”

Mullen Scales of Early Learning Adaptation for Assessment of Indian Children and Application to Tuberculous Meningitis

“…The use of MSEL is a component of a multicenter clinical trial, 'A Phase I/II Randomized, Open-label Trial to Evaluate the Pharmacokinetics, Safety and Treatment Outcomes of Multidrug Treatment Including High Dose Rifampicin with or without Levofloxacin versus Standard Treatment for Pediatric Tuberculous Meningitis' [32,33]. The main objective of the trial is to assess the effects of optimized antimicrobial treatment on functional and neurocognitive outcomes in children with TBM.…”

“…The main objective of the trial is to assess the effects of optimized antimicrobial treatment on functional and neurocognitive outcomes in children with TBM. Trial details are described elsewhere [32], but in brief, those children with possible, probable or definitive TBM who are between the ages of 6 months to 6 years undergo serial neurocognitive assessments, in addition to other evaluations. A tool for comparing neurocognition and recovery across treatment arms at various time points was needed.…”