Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial
Authors: Paradkar Mandar S , Devaleenal D Bella , Mvalo Tisungane , Arenivas Ana , Thakur Kiran T , Wolf Lisa , Nimkar Smita , Inamdar Sadaf , Giridharan Prathiksha , Selladurai Elilarasi , Kinikar Aarti , Valvi Chhaya , Khwaja Saltanat , Gadama Daphne , Balaji Sarath , Yadav Kattagoni Krishna , Venkatesan Mythily , Savic Radojka , Swaminathan Soumya , Gupta Amita , Gupte Nikhil , Mave Vidya , Dooley Kelly E ,   TuBerculous Meningitis in Kids (TBM-KIDS) Study Team, Agiwal Shivali , Ahire Rupali , Balasubramanian Usha , Bendre Manjushree , Chandane Jyoti , Chopade Kavita , Dalimbkar Shamala , Deshpande Prasad , Dhage Rajendra , Ithape Mahesh , Jadhav Varsha , Kante Sonali , Kapre Pallavi , Khan Nawshaba , Kulkarni Vandana , Madewar Renu , Meshram Shashibhushan , Muttha Kunal , Nadgeri Vaishali , Nagargoje Arti , Nagraj Amita , Nijampurkar Aparna , Onawale Prerana , Pawar Namrata , Pawar Prashant , Pradhan Neeta , Shaikh Varsha , Shaikh Zaheda , Shere Dhananjay , Wani Gouri , Kulkarni Rajesh , Rajput Uday , Ganesan Mangalambal , Arasan Gunasundari , Shankar Shakila , Mary S Stella , Karuppaiah Sureshwari , Pauline Leema , Karunakaran Pramila Snegha , Arul Priyadharshini , Ganesh Sankar , Hanna Luke Elizabeth , Ramesh K , Kannan M , Vijayakumar Ruthra , Sivakumar Surekha S , Devika K , Radhakrishnan A , Preethi A R , Rajkumar S , Saravanan N , Ramachandran Geetha , Hemanth Kumar A K , Dharman M , Sudha V , Hissar Syed , Nagarajan Valarmathi , Jennifer Linda , Supriya R , Manimegalai R , Kandan Santhanam , Maniselvi Archana , Puspha Oli , Vaishnavi S , Selvi R , Neelakandan Logeswari , Chiunda Mary , Chunga Moreen , Kamanga Madalo , Kamthunzi Portia , Kanthiti Elizabeth , Mbewe Abineli , Msiska Emmie , Mumba Noel , Zifa Phiri Ian , Palichina Victor , Sichali Dorothy , Rexroad Vivian , Hesseling Anneke , Gupta Y K , Phillips Patrick 
Published: March 2022

Abstract

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

Methods
TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) 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 prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 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 &lt; .01).

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

Clinical Trials Registration
NCT02958709.