PERFORM, CATALYST, and ChilPref studies, combined with TB-CHAMP results, provide new evidence to reduce the toll of MDR-TB in children
The results of four key studies addressing multidrug-resistant tuberculosis (MDR-TB) prevention and treatment for children were presented by the Unitaid-funded BENEFIT Kids project led by the Desmond Tutu TB Centre, Stellenbosch University, South Africa. These studies address key evidence gaps, including how to best dose TB medicines for children, that are barriers to access for optimal MDR-TB treatment.
The studies inform efforts to produce more child-friendly, better tasting medicines and formulations, to improve uptake, acceptability and outcomes among children. This work is motivated by the fact that the treatment of MDR-TB in children still lags dramatically behind recent advances in adult MDR-TB treatment.
"Children with MDR-TB are a neglected population suffering from a largely neglected disease," said Anthony Garcia-Prats, the overall Project Principal Investigator, University of Wisconsin-Madison and Stellenbosch University. "It's hard to overstate how long and harrowing the treatment journey for children with MDR-TB and their caregivers has been historically. This is not inevitable though. With the right partnerships and investment in innovative and high-priority research and development, it is possible to provide children with MDR-TB treatment that is not only effective but is also safe, well-tolerated, palatable and acceptable."
The team at Stellenbosch University with partners at University of California San Francisco pooled data from five previously published studies with more than 240 children receiving levofloxacin. This innovative approach has identified the optimal doses of levofloxacin that can inform paediatric treatment guidelines.
This work complements the project's PERFORM trial, in which researchers compared a new paediatric dispersible tablet formulation of levofloxacin to the current crushed levofloxacin adult tablets, looking at how acceptable the two medicines forms were among children. It also looked at the pharmacokinetics—how the children's bodies interact with the drug, an important consideration given that children process medicines differently than adults.
PERFORM showed that the paediatric formulation was preferred by children and their caregivers and it achieved excellent drug concentrations in young children. The research was conducted in Cape Town, South Africa. Levofloxacin is used both for prevention and treatment of MDR-TB in children.
These studies add to the findings of the phase 3 TB-CHAMP trial, which showed that levofloxacin was effective and safe at preventing MDR-TB in children exposed to an adult with MDR-TB . Data from the TB-CHAMP trial was also presented at the Union Conference.
In the CATALYST trial , researchers looked at the pharmacokinetics, safety, tolerability and acceptability of new child-friendly formulations of clofazimine and moxifloxacin, key drugs used in treating MDR-TB. This international multi-country study was conducted in India with partners from B.J. Medical College and Johns Hopkins University, the Philippines with De La Salle Medical and Health Sciences Institute, and South Africa.
The study provided data on the best doses for these medicines in children using the new child-friendly formulations. CATLYST also showed that caregivers could administer these treatments more easily to children than existing adult formulations, and provided economic data showing the costs of MDR-TB treatment regimens across the three countries.
"If we want to treat children with MDR-TB better, then we need to generate robust evidence on the safety and dosing of the relevant TB drugs, but we also need to understand the challenges that families experience when giving these medicines and the cost of the regimens within different health care systems," said Megan Palmer, CATALYST study PI, Stellenbosch University.
In the ChilPref study , researchers from Stellenbosch University and the TB Alliance evaluated which tastes of formulations of two drugs that are currently critical for MDR-TB treatment, moxifloxacin and linezolid, were preferred by children. This innovative research, conducted in South Africa, asked children themselves to give input on how they think medicines should taste.
The study confirmed the importance of taste in administering medicines to children; the currently available formulation of moxifloxacin, for example, was rejected by most children. Manufacturers now have guidance on how to produce formulations of these important medicines for MDR-TB treatment that patients will accept—improving treatment outcomes and safeguarding the health of entire families.
"Children are not simply 'little adults'; developing drug formulations for children poses a unique set of challenges and requires a concerted effort," said Graeme Hoddinott, ChilPref study PI, Stellenbosch University. "Despite improved access to child-friendly formulations in recent years, many caregivers still need to cut, break, crush and mix foul-tasting tablets that are made for adults and are not designed to disperse or dissolve. Children need child-friendly medicines."
MDR-TB does not respond to isoniazid and rifampicin, the most important "first-line" medicines used in TB treatment. Every year, an estimated 30,000 children develop MDR-TB, globally, yet fewer than 20% are diagnosed and treated, resulting in substantial preventable morbidity and mortality. When looking at all forms of TB, more than 183,000 children die annually from the disease; more than 95% of these children were under the age of 5 and did not receive any treatment.
"When developing medicines specifically meant for children, it is right to focus on safety and effectiveness—but pharmaceutical companies must also ensure that formulations taste good in addition to being easy to administer," said Anneke Hesseling, Project co-PI and Director of the Desmond Tutu TB Centre. "The most effective medicine will not work if the patient spits it out or refuses to swallow it. With a disease as serious as MDR-TB, it's critically important to make sure that children can access the most acceptable medications and regimens, and are cured as quickly as possible."
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"No child should die of TB. We are proud to work with Stellenbosch and other partners to advance research to improve treatment options for children," said Raj Taneja, MD, TB Alliance, Vice President, Pharmaceutical Product Development. "Medicines that taste better to children ultimately help adherence, ease the burden of care, improve the daily lives of children, and save lives."
The Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids) project, led by the Desmond Tutu TB Centre, Stellenbosch University, South Africa, has brought together a unique global consortium of partners to address key evidence gaps and speed access to better treatments for children affected by MDR-TB globally. With funding from Unitaid, BENEFIT Kids is generating the priority evidence on dosing, safety, effectiveness, acceptability and cost to inform WHO policy recommendations, and addressing gaps in child-friendly formulations, to improve access in the field to better MDR-TB treatment and prevention for children and their families.
