BENEFIT Kids

Overview of the different outputs forming part of the BENEFIT Kids Project

Output 1: Systematic reviews

The existing data on second-line TB drugs in children have not been optimally analysed and synthesized to produce evidence to best inform policy and clinical practice. As part of the BENEFIT Kids Project, two systematic reviews are being conducted. The systematic reviews rigorously synthesize existing data and use innovative analytic approaches to generate novel evidence with the potential to improve dosing guidance for medications and better treatment approaches for children with MDR-TB. The approach of using existing data is highly efficient and does not pose additional risk to children. These innovative analyses, involve pooling of data and use of advanced modelling techniques, will not only address current evidence gaps now, but will establish a foundation of data that can be built on in future, including supporting global data curation in collaboration with WHO. This work is charting a new approach to developing the best evidence for informing paediatric TB treatment recommendations by using existing data optimally. In addition to close coordination with WHO for this output, the BENEFIT Kids Project will  continue to engage with a broad range of stakeholders for dissemination of results and to prepare for adoption of new evidence and scale up of these improved treatment approaches.

We are collaborating with global partners who are contributing data and key expertise   and with our methodological partners at the University of California San Francisco (UCSF, Rada Savic), and the Medical Research Council of South Africa (MRC SA, Tamara Kredo)

Systematic review 1: paediatric pharmacokinetics (PK) data for 2nd-line TB drugs
As part of this systematic review, we will synthesize available data on the pharmacokinetics of second-line drugs for tuberculosis. Using state-of-the-art methods, this data will contribute to optimal dosing recommendations for MDR-TB prevention and treatment in children.  Results will be disseminated during 2023 and 2024.

Systematic review 2: paediatric MDR-TB treatment

As part of this systematic review, we  synthesize the available data on available treatment and outcomes in children treated for drug-resistant tuberculosis. This evidence is proactively shared with the WHO for consideration for uptake into paediatric dosing and treatment guidelines and initial results have already informed WHO guidelines  on the use of bedaquiline and delamanid in children in 2022.  Additional results will be disseminated during 2023. Going forward, the project will continue to support global data curation on MDR-TB treatment in children, adolescents and pregnant women.

Output 2: Clinical trials to create novel evidence for improved paediatric MDR-TB treatment
The Project is undertaking several distinct and complementary clinical trials of the pharmacokinetics and safety of key TB drugs, selected and designed to address key remaining knowledge gaps and strategies to prevent TB in young child MDR-TB household contacts, and the optimal dosing of new antiretroviral drugs in newborn babies.

PERFORM
Pharmacokinetics of lEvofloxacin FORmulations in children with MDR-TB exposure study is evaluating the pharmacokinetics and acceptability of generic levofloxacin adult tablets (crushed/dissolved) compared to novel paediatric dispersible tablets (Macleods Pharmaceuticals, Mumbai, India) in 24 children at a single site in Cape Town, South Africa. PERFORM will inform improved and evidence-based guidance on using both commercially available formulations of levofloxacin tablets in children, facilitating access to levofloxacin in young children at safe and effective doses. The lead investigator for this study is Dr Louvina van der Laan, Desmond Tutu TB Centre. This trial was completed in 2022 and results will be disseminated during 2023.

CATALYST
The Clofazimine and moxifloxacin PK, safety and AccepTAbiLitY for paediatric TB treatment (CATALYST) study is a trial of the pharmacokinetics, safety, tolerability and acceptability of new generic formulations of clofazimine and moxifloxacin in children treated for drug-resistant tuberculosis. It is a multi-country study newly available generic child-friendly formulations (moxifloxacin dispersible tablets, Micro Labs Ltd, Bangalore, India and clofazimine solid tablets, Macleods Pharmaceuticals, Mumbai, India). As of December 2022, the study was fully enrolled: 37 children with DR-TB were enrolled from 3 sites (Cape Town in South Africa, Pune in India (JHU, BJMC) and Manila in the Philippines (De La Salle University Medical Centre). In addition to the pharmacokinetic and acceptability analyses, the costs of routine paediatric MDR-TB treatment will be assessed in these three diverse settings and will inform cost-effectiveness analysis. We are coordinating closely with WHO and other stakeholders to share this new evidence to inform guideline development. We will engage with a broad range of stakeholders to disseminate results and plan for adoption and scale-up of the new treatment light of the findings. Trial follow-up will be completed during 2023 with dissemination of results to follow. The lead investigator for this study is Dr Megan Palmer, Desmond Tutu TB Centre.

TB CHAMP
TB CHAMP is a cluster-randomized, community-based, double-blind controlled trial to assess the efficacy and safety of levofloxacin vs. placebo in children below 5 years of age exposed to MDR-TB in the household. In this trial, almost 1000 children with recent household exposure to an MDR-TB source case were enrolled across 5 sites and randomized by household to receive either daily levofloxacin (15-20 mg/kg) or matching placebo for 6 months and followed for a maximum of 18 months to characterize the efficacy (incident TB disease), safety and tolerability of the treatment. The trial opened in South Africa in Quarter 4, 2017 and completed accrual in 2022. Trial results will be disseminated during 2023. Evidence for the efficacy and safety of levofloxacin in preventing MDR-TB in exposed children is expected to result in international recommendations for its use for this indication. This has the potential for substantial public health impact, as implementation would help prevent the development of MDR-TB in at-risk children. The lead investigator for this study is Anneke Hesseling (Co-principal investigators: James Seddon and Simon Schaaf),  in collaboration with the MRC CTU at UCL (PI:Dr. Trinh Duong).

DELAMANID CRUSH
The Delamanid Crush study characterized the pharmacokinetics and the acceptability of crushed or dissolved delamanid 50 mg solid tablets in 24 healthy adult volunteers to inform their use for children affected by MDR-TB. The lead investigator for this study is Dr Veronique de Jager, and the trial was implemented at TASK Applied Science in Cape Town. Results have been disseminated to WHO during 2022 and have informed delamanid dosing guidelines in children, and final data has been published.

PETITE

The PETITE study platform was established as part of the BENEFIT-Kids project to inform evidence-based guidance on the use of novel paediatric antiretroviral formulations in neonates who currently have few options for the prevention and treatment of HIV.  Adrie Bekker, Stellenbosch University, and Tim R. Cressey, Chiang Mai University, are co-leading the series of PETITE studies.

The first PETITE study evaluated the pharmacokinetics and safety of a novel fixed-dose combination granule formulation of abacavir/ lamivudine/ lopinavir/ ritonavir (4-in-1) in 16 HIV-exposed neonates enrolled at Tygerberg Hospital, Cape Town, South Africa. The higher than standard doses of abacavir and lamivudine imposed by the FDC were well tolerated but the lopinavir/ritonavir exposures were very low, thus preventing the use of this paediatric formulation in neonates in future. Given these findings, a second study assessing two separate formulations of the same three drugs (a quarter dispersible tablet of abacavir/ lamivudine once a day and 2 sachets of lopinavir/ritonavir twice a day) was conducted in 24 neonates to allow for higher dosing of lopinavir/ritonavir. This study was completed and results from this second study will be disseminated during 2023.

A third pivotal study, the PETITE Dolutegravir study, recently started enrolling neonates exposed to HIV to assess the pharmacokinetics and safety of dolutegravir in addition to standard of care antiretroviral prophylaxis. To date, 16 neonates have enrolled and the study is expected be completed during 2023.  Dolutegravir is being rolled out globally in children and data on its appropriate and safe dosing with appropriate formulations in newborn babies is urgently needed.

Output 3: Targeted formulation and market shaping work to improve the availability of child-friendly formulations of 2nd-line TB drugs

Led by TB Alliance and in partnership with Stellenbosch University, the BENEFIT Kids project is working closely with generic manufacturers to stimulate progress and ensure the development of two novel or optimized formulations of 2 key drugs, moxifloxacin and linezolid, to ensure that formulations are child-friendly and are palatable to children, the end-users. As part of this work, a study of the best tasting formulation blend of these drugs (ChilPref_ML) was successfully completed in healthy child volunteers in South Africa in 2022. The results, which will be disseminated during 2023, have informed the taste selection of these new formulations going forward.  We will continue to build on this work in future and undertake more field work on more optimal and practical delivery methods of TB medications to children.

Caption:

This video (courtesy TB Alliance) shows a representative procedure for preparation of compounded BDQ syrup suspension. This approach can make pills easier for patients to take.

BENEFIT Kids is also undertaking complementary laboratory-based work to inform the use of extemporaneous suspension formulations, prepared from widely available existing adult tablets, for treatment of children to bridge current gaps in access to paediatric formulations in the field. In addition, taste test evaluations have be conducted to understand children’s preferences of paediatric TB formulations. This will be an important bridge in some settings until child-friendly formulations are more widely available. This work is ongoing and several outputs have been disseminated and have already been shared with WHO during 2022, informing operational guidance for the practical use of these formulations in the field.