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

Paradkar, Mandar S and Devaleenal D, Bella and Mvalo, Tisungane and Arenivas, Ana and Thakur, Kiran T and Wolf, Lisa and Nimkar, Smita and Inamdar, Sadaf and Giridharan, Prathiksha and Selladurai, Elilarasi and Kinikar, Aarti and Valvi, Chhaya and Khwaja, Saltanat and Gadama, Daphne and Balaji, Sarath and Yadav Kattagoni, Krishna and Venkatesan, Mythily and Savic, Radojka and Swaminathan, Soumya and Gupta, Amita and Gupte, Nikhil and Mave, Vidya and Dooley, Kelly E and Agiwal, Shivali and Ahire, Rupali and Balasubramanian, Usha and Bendre, Manjushree and Chandane, Jyoti and Chopade, Kavita and Dalimbkar, Shamala and Deshpande, Prasad and Dhage, Rajendra and Ithape, Mahesh and Jadhav, Varsha and Kante, Sonali and Kapre, Pallavi and Khan, Nawshaba and Kulkarni, Vandana and Madewar, Renu and Meshram, Shashibhushan and Muttha, Kunal and Nadgeri, Vaishali and Nagargoje, Arti and Nagraj, Amita and Nijampurkar, Aparna and Onawale, Prerana and Pawar, Namrata and Pawar, Prashant and Pradhan, Neeta and Shaikh, Varsha and Shaikh, Zaheda and Shere, Dhananjay and Wani, Gouri and Kulkarni, Rajesh and Rajput, Uday and Ganesan, Mangalambal and Arasan, Gunasundari and Shankar, Shakila and Mary, S Stella and Karuppaiah, Sureshwari and Pauline, Leema and Karunakaran Pramila, Snegha and Arul, Priyadharshini and Ganesh, Sankar and Hanna, Luke Elizabeth and Ramesh, K and Kannan, M and Vijayakumar, Ruthra and Sivakumar, Surekha S and Devika, K and Radhakrishnan, A and Preethi, A R and Rajkumar, S and Saravanan, N and Ramachandran, Geetha and Hemanth Kumar, A K and Dharman, M and Sudha, V and Hissar, Syed and Nagarajan, Valarmathi and Jennifer, Linda and Supriya, R and Manimegalai, R and Kandan, Santhanam and Maniselvi, Archana and Puspha, Oli and Vaishnavi, S and Selvi, R and Neelakandan, Logeswari and Chiunda, Mary and Chunga, Moreen and Kamanga, Madalo and Kamthunzi, Portia and Kanthiti, Elizabeth and Mbewe, Abineli and Msiska, Emmie and Mumba, Noel and Zifa Phiri, Ian and Palichina, Victor and Sichali, Dorothy and Rexroad, Vivian and Hesseling, Anneke and Gupta, Y K and Phillips, Patrick (2022) Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial. Clinical Infectious Diseases, 75 (9). pp. 1594-1601. ISSN 1058-4838

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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 < .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.

Affiliation: ICMR-National Institute for Research in Tuberculosis
Item Type: Article
Uncontrolled Keywords: pediatric tuberculous meningitis; neuropsychological; clinical trial; levofloxacin; high-dose rifampicin
Subjects: Tuberculosis > Clinical Research
Divisions: Clinical Research
Depositing User: Dr. Rathinasabapati R
Date Deposited: 29 Mar 2023 10:11
Last Modified: 29 Mar 2023 10:11
URI: http://eprints.nirt.res.in/id/eprint/1896

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