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'25 at 25': Conducting the first large international randomised controlled trial on tuberculosis treatment for children

07 Aug 2024

More than a million children fall ill with tuberculosis (TB) each year around the world. Yet few trials are conducted to inform treatment for these children. This is partly because children are harder to diagnose with the disease. This means that treatment recommendations are based on evidence from trials conducted in adults. There may be important differences in how children respond to treatment.  

As part of our '25 at 25' series, we look back at the SHINE trial, which sought to address this evidence gap. This landmark study was the first randomised controlled trial to assess the length of treatment needed for children with TB.  

Children often have milder forms of the disease than adults (two thirds have ‘minimal’ disease), and generally do well if they are diagnosed and treated. TB treatments involve taking a combination of drugs for several months. At the time SHINE was developed, guidelines recommended that children with drug-sensitive TB are treated for six months. However, taking several pills every day for six months can be difficult for children and carers. Some TB drugs interact with other drugs, such as those used for treating HIV, making treatment even more complicated. Reducing the length of time children need to take pills for could make treatment easier for children and carers, as well as reducing costs to patients and the health system. 

The SHINE trial took place in South Africa, Uganda, Zambia and India. 1204 children with minimal TB took part in the trial. Minimal TB is TB that is smear negative (so cannot be detected in sputum using a microscope) and non-severe. They were randomised to receive either: 

  • six months of treatment, with eight weeks of the drugs isoniazid, rifampicin, pyrazinamide (and ethambutol in some countries, depending on national guidelines), followed by 16 weeks of isoniazid and rifampicin 
  • four months of treatment, with eight weeks of the drugs isoniazid, rifampicin, pyrazinamide (and ethambutol in some countries, depending on national guidelines), followed by eight weeks of isoniazid and rifampicin 

Children in the trial were followed up for 72 weeks.  

SHINE found that the four month treatment was as good as the standard six month treatment for children with minimal TB. There was no difference between the six months and four months groups in terms of proportion with an unfavourable outcome, or deaths. Unfavourable outcomes were defined as treatment failure, loss-to-follow-up while on treatment, TB recurrence or death by 72 weeks. Most of the unfavourable outcomes in the trial were relapse of TB. Side-effects related to treatment were few, and similar across both groups. The shorter treatment also had the advantage of reducing costs to the health system. 

These results mean that around two thirds of children could potentially be safely and effectively treated with four months of treatment rather than six months. The World Health Organisation quickly updated their guidelines based on evidence from SHINE trial, to recommend four months of treatment for children with non-severe disease. The SHINE results have also been incorporated into treatment guidelines in countries including Zambia, Kenya, the UK and Spain. 

SHINE also demonstrated that it is possible to do high quality randomised controlled trials in children with TB, despite the challenges diagnosing them. Based on the work of the SHINE trial, guidance has been developed by the World Health Organisation and the International Union Against TB and Lung Disease to help health workers identify children with minimal TB who could benefit from shorter treatments.  

It is important that children’s treatment is informed by evidence from trials conducted in children – they are not small adults, and their bodies may respond differently to diseases or treatments than adults. Yet children are often excluded from clinical trials, meaning there are often long delays before they can benefit from new medicines. The MRCCTU at UCL has a proud history of carrying out trials in children with infectious diseases, to help them access the best available treatments. 

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