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

Abstract

BackgroundTuberculosis (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/designSHINE 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.DiscussionAlthough 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.Trial registrationInternational Standard Randomised Controlled Trials Number: ISRCTN63579542, 14 October 2014.Pan African Clinical Trials Registry Number: PACTR201505001141379, 14 May 2015.Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2608-5) contains supplementary material, which is available to authorized users.

Accuracy of Xpert Ultra in Diagnosis of Pulmonary Tuberculosis among Children in Uganda: a Substudy from the SHINE Trial

“…SHINE (shorter treatment for minimal TB in children) is a randomized trial of therapy shortening for minimal tuberculosis with new WHO-recommended fixed-dose-combination drugs in African and Indian HIV-positive and HIV-negative children (International Standard Randomised Controlled Trials no. ISRCTN63579542) (13). Minimal TB in children is defined as a form of nonsevere, symptomatic, smear-negative TB, including extrathoracic lymph node TB, intrathoracic uncomplicated lymph node TB, and other nonsevere forms of pulmonary TB as per an established classification system (14).…”

“…The trial is evaluating 4 versus 6 months of standard treatment for children with nonsevere drug-susceptible minimal TB disease. Details of the study design and population were described previously (13). Symptomatic children who provided samples in the trial screening process but were not subsequently enrolled in the clinical trial were also eligible for inclusion in this substudy.…”

Acceptability of a first-line anti-tuberculosis formulation for children: qualitative data from the SHINE trial

“…22 Study design SHINE is a randomised, open-label, non-inferiority trial comparing the safety and efficacy of a 6-vs. 4month ATT regimen using the WHO-recommended FDC in 1200 HIV-infected and non-infected children in South Africa, Zambia, Uganda and India. 23 Children aged 0-16 years, weighing 3 kg, and with symptomatic non-severe TB, regardless of HIV status, were eligible to participate.…”

Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review

“… 174 , 175 Higher TB treatment dosing schedules should be considered and are currently being investigated in children with and without HIV. 176 , 177 Data about the effect of HIV infection on PK of first-line TB drugs in adults and children are still inconclusive. 27 In children who are HIV co-infected, significant decreases in exposure of rifampicin and ethambutol were seen, regardless of ART use.…”