Mandar S Paradkar1,2, D Bella Devaleenal3, Tisungane Mvalo4,5, Ana Arenivas6, Kiran T Thakur7, Lisa Wolf8, Smita Nimkar1,2, Sadaf Inamdar1,2, Prathiksha Giridharan3, Elilarasi Selladurai9, Aarti Kinikar1,10, Chhaya Valvi1,10, Saltanat Khwaja1,2, Daphne Gadama4, Sarath Balaji3, Krishna Yadav Kattagoni3, Mythily Venkatesan3, Radojka Savic11, Soumya Swaminathan12, Amita Gupta8, Nikhil Gupte1,2,8, Vidya Mave1,2,8, Kelly E Dooley8. 1. BJ Government Medical College-Johns Hopkins Clinical Research Site, Pune, India. 2. Johns Hopkins India, Pune, India. 3. Department of Clinical Research, ICMR-National Institute for Research in Tuberculosis, Chennai, India. 4. UNC Project Malawi, Lilongwe, Malawi. 5. Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, NC, USA. 6. Cleveland Clinic Foundation, Neurological Institute, Section of Neuropsychology, Cleveland, OH, USA. 7. Department of Neurology, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York, NY, USA. 8. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 9. Institute of Child Health and Hospital for Children, Chennai, India. 10. Department of Pediatrics, BJ Government Medical College, Pune, India. 11. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. 12. World Health Organization, Geneva, Switzerland.
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.
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.