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

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.

Nearly a million children develop tuberculosis (TB) each year and it is acknowledged that young children are at a high risk of developing the most severe forms of disease such as tuberculous meningitis (TBM). TBM is associated with significant mortality and functional impairment and the current treatment regimen advised by the WHO in children is to give four anti-TB drugs for two months (isoniazid (H), rifampicin(R), pyrazinamide(Z) and ethambutol (E)) followed by two drugs (H and R) for ten months:2HRZE10HR. There is emerging evidence that it may be possible to achieve similar, or better, outcomes using a shorter more enhanced regimen. Aspirin may also have a role in the treatment of TBM due to its anti-inflammatory and anti-thrombotic properties and be associated with improved functional status. The SURE trial is designed as a 4-year phase III, part-blinded factorial randomised controlled trial for the treatment of TBM in children. The first randomisation (1:1) will be a non-inferiority open-label design to evaluate whether a 6 month intensive (at revised higher dosages) regimen (6HRZL) is non-inferior to the current 12 month WHO-recommended regimen (2HRZE10HR). The second (1:1) will be placebo-controlled, blinded superiority design to evaluate the efficacy of low-dose aspirin on functional status. 400 children will be recruited from 8 centres across Africa and Vietnam. The trial will also address other important questions including cost-effectiveness and acceptability. The primary endpoint for the first randomisation is all-cause mortality at 12 months post randomisation; and for the second randomisation is functional status (measured by a modified Rankin score) at 12 months post randomisation. Should the shorter regimen be at least as good as the longer regimen, and/or should the provision of aspirin be safe and associated with improved neurological outcomes, then we would anticipate these would translate rapidly into international guidance.

Who might benefit from this research?
This trial will benefit:
- Children diagnosed with TB meningitis (TBM), including those with HIV, and their families
- Trial sites
- Ministries of health and national TB programs (NTPs)
- International policymakers
How might they benefit from the research?
Children with TBM and their families: TBM is the most devastating kind of TB and is associated with significant mortality and morbidity. Survivors have high rates of functional impairment. The human cost for children with motor, visual and hearing disability, and behavioural and learning difficulties is substantial. In addition, there is high financial long-term cost to families and society. If the proposed study interventions (short intensified treatment and/or aspirin) lead to improved outcomes, this could improve health and have potentially have a lifelong positive impact on quality of life for a large number of affected children worldwide, reducing the disability burden in communities.
TBM is currently treated for 12 months. Giving the medications to young children can be a daily challenge for families. If we find that the length of treatment can be safely halved, this will spare children 6 months of treatment, with associated cost, toxicity and, in HIV-positive children, drug-drug interactions and risk of virological failure.
Children and their carers may need to travel regularly to be observed taking their treatment, collect medications and be clinically assessed, resulting in disruption of family lives, transport costs and loss of earnings. Reducing the duration of treatment could ameliorate these problems.
The potential impact of this study is far reaching; the international collaboration across sub-Saharan Africa and East Asia mean the results will be widely generalizable.
Trial sites: The study will give an opportunity for local scientists and medical professionals to gain research experience. This will help to retain the research expertise in the countries and contribute to advancing of scientific knowledge applicable to local populations. It will also sensitise local staff about TBM to raise awareness, potentially leading to earlier recognition and diagnosis.
Ministries of health and NTPs: If the study finds that the enhanced regimen is as good as the current 12-month treatment, this could reduce costs. This could allow NTPs to treat more children for the same budget. If we demonstrate improved functional status in children, this will lead to long-term economic impact for both families and the healthcare system.
We plan to use fixed dose combination tablets which were recently endorsed by the WHO, and are now available through the Global Drug Facility. If the new FDCs are found to be appropriate for TBM, it will make treatment easier and simplify procurement (as the same FDCs can be used for all clinical forms of TB disease in children). This will assist with swift implementation.
Health economics evaluation and qualitative research on acceptability of treatment among patients/families and health workers will be undertaken to inform policymaking and implementation the findings of the research.
International policymakers: This trial examines the questions identified as priority research gaps by WHO. The current guidance is based on limited evidence. Our trial will provide solid evidence for the appropriate clinical management of TBM in children. Should the study results demonstrate that the enhanced regimen is safe and as good as the standard regimen, and/or the use of aspirin is associated with improved functional outcome then we would anticipate rapid transfer of these interventions into WHO and national TB programme guidance and subsequently into clinical practice. Should these two interventions not demonstrate the anticipated results, it would provide compelling evidence that the standard of care should be maintained until better treatment options are identified.