MICA: randomized trial of therapy shortening for minimal TB with new WHO-recommended doses and FDC drugs in African/Indian HIV+/HIV- children

Tuberculosis (TB) continues to be a major health problem in many countries. Of the estimated 9 million new TB cases every year across the world, about one million (11%) are in children with the majority in Africa and South East Asia. Based largely on research conducted only in adults, standard treatment for childhood TB is given for 6 months irrespective of how severe the disease is. Children often have mild forms of TB and it is likely that they could be successfully treated for less than 6 months. This would have major advantages for the child, their family and carers, and for over-burdened health systems, by reducing the number of clinic visits children need to make to take their drugs. Shorter treatment would be particularly advantageous for children who also have HIV and need to take seven or eight drugs at the same time, often leading to problems with drug side effects and difficulty taking all their pills at the right time. It could also reduce the cost of treating mild forms of TB in children, freeing up money to be used for treating other people and diseases.

A trial in adult patients with mild TB disease in Hong Kong showed that they did equally well if they took four or six months of treatment. However, this study has not been repeated and no trial has studied the length of treatment needed for children with mild disease, which accounts for more than half the cases of TB worldwide in children.

TB is a much neglected research area in children. In this trial, children aged twelve or younger with mild forms of TB disease who are considered by a doctor to need treatment for TB will be randomised (i.e. given by chance) to receive either the standard six months treatment recommended by international guidelines (the 'control group'), or the same drug regimen but given only for four months.

We plan to use new dissolvable mini-pills containing three anti-TB drugs, at doses which have been recently recommended by the WHO. Pharmacokinetic studies (measuring levels of drug in the blood) will be performed at the start of the trial in order to confirm, as soon as possible, whether these new baby pills have the right doses of each drug, as well as whether the weight band tables suggested by the WHO, are correct (i.e. result in the right amount of drug in the blood).

We will also check drug blood levels to ensure that the TB drugs are not causing the levels of HIV drugs to be too low, as we know these medicines interact with each other. This is an important research gap identified by the WHO HIV guidelines group.
We will also do some research asking healthcare workers about how they use dosing tables for children, as the current ones for anti-TB drugs are different from the ones for anti-HIV drugs. This could help to harmonise these better, to make it easier for healthcare workers to treat children who have both HIV and TB.

TB in children is most common in places where the resources available for health care are very restricted. This means the cost of different ways of treating TB is an important issue. The health economics work we are doing as part of this trial will help to show the budget impact of adopting a shorter regimen, if it is as good as the standard one, or, if it is not as good, then whether the 6 months treatment provides value for money.

A total of 1200 children will be enrolled from clinical centres in Africa and Asia. Children with TB disease that is resistant to rifampicin, children with serious forms of TB or with advanced HIV disease will be excluded from the trial. We will follow all children for at least 18 months to check how many get TB again (relapse or get infected with a new strain of TB). The main objective of the trial is to determine whether treatment shortened to 4 months is as good as the 6 months current standard. We will also be able to analyse whether the levels of anti-TB drugs in the blood relate to both drug side effects and long-term response to TB and HIV treatment.

There is wide acknowledgement that TB in children has been neglected; due to lack of research, recommendations are frequently extrapolated from evidence in adults. TB in children differs from adults in important ways: although due to more immature immune systems, young children more often have disseminated disease, 60% childen have non-severe forms of primary TB disease including hilar/cervical lymphadenopathy with/out minimal parenchymal disease which, unlike adults, is paucibacillary and sputum smear negative. Key research questions relevant to these children include: (1) can treatment be shortened from the standard 6-month period used in sputum smear+ adults?; (2) what are the optimal doses of anti-TB drugs and their ratios in fixed-dose-combination 'baby pills' (FDCs) (3) how should treatment doses be adjusted when treating TB and HIV together in order to overcome known drug-drug interactions. The SHINE trial is designed as a 3-year randomised phase III clinical endpoint non-inferiority trial of 4- versus 6-months first-line daily treatment with anti-TB drugs in new WHO-recommended doses/ratios, in 1200 African and Indian children, with/without HIV infection and with limited pulmonary and/or extrapulmonary TB disease. Through nested pharmacokinetic substudies, we will determine if the WHO-proposed new drug doses and drug ratios for newly designed FDCs for children are appropriate when dosed according to WHO-proposed weightband tables. We will also assess interactions between rifampicin and relevant ARVs in HIV-TB co-infected children. Qualitative and economic sub studies will address implementation/ acceptiblity issues for families and healthcare workers of new drug dosing recommendations and the cost implications of treatment shortening. We will work closely with WHO and other bodies concerned with the implementation of evidence-based guidance for treatment for children with TB and TB/HIV co-infection worldwide.

Who will benefit from this research & how?
This trial will benefit national TB programs (NTPs), the WHO, the Global Drug Facility (GDF) and the Global Fund, healthcare workers in resource-limited countries, and most importantly, TB-diseased children and their families.
Policymakers such as WHO will benefit from this research in several ways. The lack of evidence on TB treatment for children makes it difficult to develop evidence-based recommendations for children, leading to recommendations based on extrapolated evidence from adults to children. Obtaining PK data on new FDCs in children will encourage manufacturers to develop FDCs in response to the WHO call to manufacturers (January 2013). If the shorter treatment duration is non-inferior the GDF and NTPs will be able to treat more children for the same budget.
Ministries of Health will benefit from this research in several ways. We plan to undertake qualitative research to address questions about how healthcare workers use weight band tables, particularly for HIV-infected children on both anti-TB and antiretroviral therapy (ART) as these are currently different. This could inform future harmonisation of weight band tables for HIV-infected children with TB that could simplify paediatric TB treatment and make it easier to integrate with HIV programmes. If the PK data finds the new FDCs to be appropriate, this will simplify implementation of TB treatment, with supply chains and health workers no longer having to deal with separate anti-TB drugs. If the shorter treatment duration is non-inferior it will reduce the costs of treating children with TB and reduce the number of health centre visits required.
The work on weight band tables for the trial could make it easier for healthcare workers to know how much drug to give to children. If FDCs are found to be appropriate, it will further simplify treatment and make it more child-friendly. If the shorter treatment duration is found to be non-inferior, it will reduce the work burden on health workers. The shorter treatment may also make it easier for health workers to encourage treatment adherence.
Approximately 60% children with intrathoracic TB have minimal disease. These children are currently treated for 6 months. If we find that this can safely be reduced to 4 months, it will benefit these children and their caregivers. Reducing the pill burden by two months should make adherence to treatment easier, particularly for those who are also on ART. Reducing the length of time that children are on both TB treatment and ART may help to reduce drug-drug interactions and toxicity. It also reduces the number of visits children have to make to the health facility, which will help reduce travel costs and the loss of caregiver productivity. The results of the research will enable guidelines to be based on better quality evidence, which can help to ensure that children get the best treatment possible. The acceptability research will help to inform which formulations are used which may help to improve adherence.
Communities where incidence of TB in children is high will benefit from this research, if we find that treatment length can be reduced, as this will free up financial and human resources to treat more patients and other conditions.
Pharmaceutical companies will benefit from PK data generated by this trial, as it will help inform their development of FDCs for children, and support the use of their drugs if the results are positive.
The timing of these benefits will depend on how long it takes for WHO and NTPs to update their guidelines. However, the involvement of WHO, UNITAID, DNDi and TB Alliance in the design and running of this trial will hopefully speed the uptake into international guidelines, which will then influence national guidelines. Market research and close collaboration with regulatory agencies and WHO facilitated by TB Alliance's recent UNITAID paediatric TB grant will aid in this process.