Short enhanced anti-tuberculosis and anti-thrombosis treatment for children with tuberculous meningitis

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Children who come into contact with an adult who has tuberculosis (TB) are at a high risk of getting TB themselves. Globally, nearly a million children get TB each year. As well as being at high risk of getting TB, young children are especially prone to getting severe TB, which affects the brain. This is called TB meningitis (or TBM). About one in five children who get TBM die of the disease. Of the children who survive, half will have some kind of disability. As well as this tragedy for the child, there is a large personal and financial cost to families who look after these children, often for many years. Health systems and societies are also affected. The World Health Organization currently advises 12 months of treatment for children with TBM. They recommend that children with other sorts of TB have 6 months of treatment. This advice is not based on good quality evidence. Experts have been calling for a study to be done to try to find out if it is safe and effective to treat children with TBM for six months. Halving the treatment time would probably have large benefits for families and health systems. Researchers in South Africa have investigated treating children for six months, by giving them slightly different drugs and at higher doses. This means higher drug concentrations are achieved in the brain. The outcomes for these children seem at least as good as the outcomes in other places where 12 months of treatment are given. However, we cannot be sure if it is safe and effective because it has never been tested in a randomised trial. The drug aspirin has been used for many years for fever and pain. It is also known to make the blood clot less readily. It is used widely as a treatment for adults who have had heart attacks or strokes to prevent blood clots. Much of the damage in children with TBM is caused by stroke. Aspirin (in addition to TBM treatment) may help to reduce this damage. Two studies have looked at this issue in children. One study showed that aspirin was beneficial and one showed that it was not. Both studies were quite small and doctors remain unsure whether to use aspirin.We plan to carry out a randomised trial to answer two questions. 1) Is it safe and effective to treat children with TBM for 6 months as opposed to 12 months? We plan to see if children treated for 6 months have outcomes that are as good as children treated for 12 months. The children treated for 12 months will receive the currently advised treatment. The children treated for 6 months will receive higher dosages of the drugs and one drug that is different. 2) Does aspirin reduce the risk of disability in children with TBM? We plan to give half the children aspirin and the other half a placebo (sugar pill) so that neither they nor the study team knows which child is receiving which treatment.We will monitor all children for side effects. We will also investigate whether these two approaches are acceptable to families and what the financial implications are for both families and for health systems.We will need about 400 children in the trial to answer these questions. We will carry out the trial in Uganda, Vietnam, Zambia and Zimbabwe. By doing the trial in many different places, we can be confident that any results that we find will be relevant for children all over the world. If either shortening treatment or adding aspirin is safe and effective, the results of this trial could improve how doctors treat children with TBM across the world.