Randomized Clinical Trial of High Dose Rifampicin with or without Levofloxacin versus Standard of Care for Paediatric Tuberculous Meningitis: The TBM-KIDS Trial

ARTICLE: Randomized Clinical Trial of High Dose Rifampicin with or without Levofloxacin versus Standard of Care for Paediatric Tuberculous Meningitis: The TBM-KIDS Trial

AUTHORS: Mandar S Paradkar, D Bella Devaleenal, Tisungane Mvalo, Ana Arenivas, Kiran T Thakur, Lisa Wolf, Smita Nimkar, Sadaf Inamdar, Prathiksha Giridharan, Elilarasi Selladurai, Aarti Kinikar, Chhaya Valvi, Saltanat Khwaja, Daphne Gadama, Sarath Balaji, Krishna Yadav Kattagoni, Mythily Venkatesan, Radojka Savic, Soumya Swaminathan, Amita GuptaNikhil GupteVidya MaveKelly E Dooley, TBM-KIDS Study Team

JOURNAL: Clin Infect Dis. 2022 Mar 15;ciac208. doi: 10.1093/cid/ciac208. Online ahead of print.

Abstract

Background: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. . In adults, high-dose rifampicin may reduce mortality. Fluoroquinolones' role remains unclear. There have been no antimicrobial treatment trials for pediatric TBM.

Methods: TBM-KIDS (NCT02958709) was a Phase II open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (a) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, Arm 1); (b) high-dose rifampicin and levofloxacin (R30HZL, Arm 2); or (c) standard-dose rifampicin and ethambutol (R15HZE, Arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL).

Results: Of 2487 children pre-screened, 79 were screened, and 37 enrolled. Median age was 72 months. 49%, 43%, and 8% had Stage I, II, and III disease. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in Arms 1, 2, and 3, with one death (Arm 1) and six early treatment discontinuations (4 in Arm 1, 1 each in Arms 2 and 3). By Week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in Arm 1 than Arm 3 in fine motor, receptive language, and expressive language domains (p<0.01).

Conclusions: In a pediatric TBM trial, functional outcomes were excellent overall. The trend towards higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial.

Keywords: clinical trial; high-dose rifampicin; levofloxacin; neuropsychological; pediatric tuberculous meningitis.

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