Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial

Post Date: 
2018-04-19
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Publication: 
Trials
Summary: 
Background
Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed.
 
Methods/Design
SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations.
 
Discussion
Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB.
 
Recruitment to the SHINE trial begun in July 2016; results are expected in 2020.
Citation: 
Chabala C, Turkova A, Thomason MJ, Wobudeya E, Hissar S, Mave V, van der Zalm M, Palmer M, Kapasa M, Bhavani PK, Balaji S, Raichur PA, Demers AM, Hoddinott G, Owen-Powell E, Kinikar A, Mulenga P, Aarnoutse R, McIlleron H, Hesseling A, Crook AM, Cotton M, Gibb DM on behalf of the SHINE trial team. Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial. Trails. 2018 Apr 19:19;237.
Collaborators: 
  • University Teaching Hospital, Children’s Hospital, Lusaka, Zambia
  • Desmond Tutu TB Centre, Stellenbosch University, Cape Town, South Africa
  • Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, London, UK
  • Makerere University-John Hopkins University Care Ltd, Kampala, Uganda
  • India Council of Medical Research, National Institute for Research in Tuberculosis, Chennai, India
  • India Institute of Child Health and Hospital for Children, Chennai, India
  • Radbound University Medical Center, Nijmegen, The Netherlands
  • University of Cape Town, Cape Town, South Africa
  • Family Infectious Diseases Clinical Research Unit, Stellensbosch University, Cape Town, South Africa