TB-CHAMP trial finds first-ever safe and effective treatment to prevent multidrug-resistant TB in children

19 Dec 2024

The oral antibiotic levofloxacin, taken once daily for six months, can substantially reduce the risk of developing drug-resistant tuberculosis (TB) in children, according to landmark results from the TB-CHAMP trial reported in the New England Journal of Medicine this week.

Levofloxacin reduced the risk of multidrug-resistant (MDR) TB disease in children by 56%. The trial also showed that levofloxacin given over six months was safe and well tolerated.

In recent years, scientists have made major advances in treating MDR-TB disease more safely and effectively in adults. But until now, there has been no rigorous evidence from clinical trials on how to prevent MDR-TB. This first-of-its-kind evidence has the potential to protect millions of children across the world.

The TB-CHAMP trial was conducted in South Africa, which has a high burden of TB and MDR-TB. It was led by Stellenbosch University, and the MRC Clinical Trials Unit at UCL were responsible for the trial management and statistical analysis.

The trial focused mainly on children below 5 years of age. Young children exposed to TB have a high risk of progressing to active TB disease and developing severe forms of the disease.

TB-CHAMP involved 922 children who had been exposed to an adult with MDR-TB in their household. In the trial, 453 children were given levofloxacin, while the other 469 children were given a placebo instead.

Only five children (1.1%) in the levofloxacin group developed MDR-TB, compared to 12 (2.6%) who were given a placebo.

Levofloxacin was generally well accepted by children and caregivers, and there were very few side effects from the medicine. Specifically, joint pain and tendonitis, traditionally a concern, were very uncommon in children receiving levofloxacin.

Over 450,000 people develop MDR-TB each year, which can be devastating for patients and their families. The TB-CHAMP trial used randomisation by household, so all children eligible in each household received the same intervention.

Prevention strategies for TB are usually found to be cost-effective. The TB-CHAMP trial included compelling work on cost and impact. For every 1,000 children offered this regimen, given a 2.5% risk of developing MDR-TB disease, there was a total health saving of $11.3 million, a total health gain of 30 healthy life years, 15 fewer MDR-TB cases and one less death.

A similar study conducted in Vietnam, the VQUIN trial which focused on adults and adolescents, had similar findings and is also reported in the New England Journal of Medicine.

In a unique collaboration, investigators from the TB CHAMP and V-QUIN trials combined the data from their trials across paediatric and adult populations to jointly inform new guidelines on MDR-TB prevention.

Using both traditional meta-analysis and novel Bayesian analysis, the teams combined data from trials in two populations with novel methodology developed at the MRC CTU at UCL. These joint combined trial findings are reported this week in NEJM Evidence.

In September 2024, the World Health Organization recommended levofloxacin for MDR-TB preventive treatment in children, adolescents and adults, based on a review of this trial evidence. This efficient, collaborative analysis strategy highlights the advantages of proactive data sharing and innovative methods to pool data. It ensured that evidence from adults and children could simultaneously impact global guidelines and improve access in the field to all of those at risk of developing MDR-TB.

TB remains one of the top causes of death in children globally and is one of the top killers of children below 5 years of age. Fewer than 20% of children with MDR-TB are currently diagnosed and treated, making them one of the most neglected populations affected by TB.

Many of these children with MDR-TB have been in close contact with someone with infectious MDR-TB. Identifying these children and the rest of their households, screening them for TB and offering them preventive treatment will be critical to finding more cases and preventing MDR-TB.

The TB-CHAMP trial was funded by Unitaid, under the BENEFIT Kids project at Stellenbosch University. Unitaid accelerates access to innovative health products and lays the foundations for their scale-up by countries and partners. The trial was also funded by the South African Medical Research Council and the UKRI Medical Research Council through a grant to Stellenbosch University, with support from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the Global Challenges Research Fund, the Medical Research Council and Wellcome, as part of the EDCTP2 programme supported by the European Union.

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