The BENEFIT Kids Project
Children affected by multi-drug-resistant tuberculosis (MDR-TB) are the most underserved population with tuberculosis globally.
There are currently an estimated two million children newly infected with MDR-TB strains globally each year. An estimated 30,000 children develop MDR-TB disease each year, but less than 5% are treated for this disease. For children who are able to access treatment, current regimens are long, complex, toxic, poorly tolerated and not acceptable to children and families. Effective and safe child-friendly treatment and prevention for MDR-TB in children is therefore a priority. The current lack of high-quality evidence on the treatment of MDR-TB in children needs to be addressed urgently.
Lack of access to better MDR-TB treatment and prevention results in substantial preventable morbidity and mortality in children.
Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids) is a 3-year project (2019-2022) designed to address critical gaps in research and products in order to improve the treatment and prevention for children affected by MDR-TB. The project was made possible with support and funding from Unitaid, an international organisation that invests in innovations to prevent, diagnose and treat major global health problems, including HIV/AIDS, malaria and tuberculosis, more quickly, affordably and effectively.
The overall goal is to reduce morbidity and mortality of children affected by MDR-TB through better access to improved MDR-TB prevention and treatment options. In order to do this, BENEFIT Kids will:
- Evaluate and synthesize existing treatment evidence: Conduct two systematic reviews and individual patient data meta-analysis, to pool all available data on MDR-TB medications and treatment outcomes in children. The goal is to generate evidence on improved paediatric dosing and treatment strategies.
- Generate new evidence: Conduct four clinical trials on the prevention and treatment of children affected by MDR-TB to generate urgently needed new pharmacokinetics, safety, acceptability and efficacy data. We will also address highly vulnerable neglected children affected by TB and HIV, by conducting a clinical trial of the pharmacokinetics and safety of new fixed-dose combination antiretroviral medication in high-risk neonates.
- Develop new formulations: In partnership with the TB Alliance, develop multiple new affordable child-friendly formulations of effective new and existing MDR-TB medications. In addition, we will work on market shaping and creation of demand to ensure that these treatments reach children in the field.
Working in close collaboration with the World Health Organisation (WHO), the project will submit all synthesized and all newly generated evidence for MDR-TB prevention and treatment to inform international guideline development. The BENEFIT Kids project will assist in sensitizing key partners and national treatment programmes, funders, industry and civil society for the rapid adoption of new evidence and products.
The BENEFIT Kids Project focus countries are South Africa, India and the Philippines.
Our partners are the TB Alliance (United States), University of California San Francisco (United States), Johns Hopkins University (United States), De La Salle University Medical Centre (Philippines), Byramjee Jeejeebhoy Medical College (India), Uppsala University (Sweden) and Chiang Mai University (Thailand).
Children deserve better care and treatment. Through BENEFIT Kids, Stellenbosch University and its global partners will catalyse better treatment and prevention globally for children affected by MDR-TB.
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 will be conducted. The systematic reviews will 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, which 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. This work will chart a new approach to developing the best evidence for informing paediatric TB treatment recommendations. This new evidence will be proactively shared with the WHO for consideration for uptake into paediatric dosing and treatment guidelines. In addition to close coordination with WHO for this output, the BENEFIT Kids Project will 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.
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. Dr Vivian Cox will lead the review with the support of a larger team based at Stellenbosch University and with our partners at the University of California San Francisco (UCSF, Rada Savic), and the Medical Research Council of South Africa (MRC SA, Tama Kredo).
Systematic review 2: paediatric MDR-TB treatment
As part of this systematic review, we will synthesize the available data on available treatment and outcomes in children treated for drug-resistant tuberculosis. Dr Vivian Cox will lead this review with the support of a larger team based at Stellenbosch University and our partners at University of California San Francisco (UCSF, Rada Savic) and the Medical Research Council of South Africa (MRC SA, Tamara Kredo).
Output 2: Clinical trials to create novel evidence for improved paediatric MDR-TB treatment
The Project will undertake four distinct and complementary clinical trials of the pharmacokinetics and safety of key TB drugs, selected and designed to address key remaining knowledge gaps. We will also complete a pivotal trial on the efficacy and safety study of oflevofloxacin for the prevention of TB in young child MDR-TB household contacts.
Pharmacokinetics of lEvofloxacin FORmulations in children with MDR-TB exposure study will evaluate the PK and acceptability of generic levofloxacin adult tablets (crushed/dissolved) compared to 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 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.
The Clofazimine and moxifloxacin PK, safety and AccepTAbiLitY for paediatric TB treatment (CATALYST) study is a phase I/II trial of the PK, 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 of the PK, acceptability of newly available generic child-friendly formulations (moxifloxacin dispersible tablets, clofazimine solid tablets, Macleods Pharmaceuticals, Mumbai, India). Approximately 40 children <15 years of age routinely treated for MDR-TB will be enrolled in Cape Town, South Africa, and in Pune, India (JHU, BJMC) and in the Philippines (De La Salle University Medical Centre). In addition, costs of routine paediatric MDR-TB treatment will be assessed in these three diverse settings and will inform cost-effectiveness analysis. We will coordinate closely with WHO ad 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. The lead investigator for this study is Dr Megan Palmer, Desmond Tutu TB Centre.
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, 1,009 young children with recent household exposure to an MDR-TB source case are enrolled 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 is recruiting children at three well-established community sites in South Africa: Desmond Tutu TB Centre, Cape Town; Shandukani in Johannesburg with the Wits Reproductive Health and HIV Institute (Site PI: Lee Fairlie); and PHRU Matlosana in Klerksdorp (Site PI: Neil Martinson). As of March 2020, 553 participants had been enrolled. 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 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), with support from MRC CTU at UCL (PI: Di Gibb) and South African sites
The Delamanid Crush study will characterize the PK 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 will be Dr Veronique de Jager, and the trial will be implemented at TASK Applied Science in Cape Town.
The PETITE study will evaluate the PK and safety of abacavir/ lamivudine/ lopinavir/ ritonavir (4-in-1) fixed-dose combination granule formulation in HIV-exposed neonates. Approximately 50 HIV-exposed neonates in two cohorts (24 per cohort) will be enrolled at Tygerberg Hospital, a large tertiary hospital in Cape Town, South Africa. This will inform the evidence-based guidance on use of this new formulation in neonates who currently have few antiretroviral treatment options. The lead investigator for this study is Adrie Bekker, Stellenbosch University, with support from Dr Tim Cressey at Chiang Mai University in Thailand.
Output 3: Targeted formulation and market shaping work to improve the availability of child-friendly formulations of 2nd-line TB drugs
Led by the TB Alliance, the BENEFIT Kids project will work closely with generic manufacturers to stimulate progress and ensure development of three novel or optimized child-friendly formulations suited for administering to children: bedaquiline, linezolid and moxifloxacin.
The project will also undertake lab-based work to inform the use of extemporaneous suspension formulations, prepared from widely available existing adult tablets, for treatment of children. This will be an important bridge in some settings until child-friendly formulations are more widely available.
In addition, the BENEFIT Kids Project will work closely with the WHO and encourage market stability, galvanize demand and engage in targeted market shaping activities at both the global and national levels, to overcome barriers to adoption, speed up regulatory approvals, increase demand and work to prepare for eventual scale-up of these new formulations.
The BENEFIT Kids Project: An update so far
The BENEFIT Kids Project, or Better Evidence and Formulations for Improved MDR-TB Treatment for Children, is a Unitaid-funded project aimed at contributing to reduced morbidity and mortality of children with MDR-TB through better access to improved prevention and treatment. The study, launched in 2019, has made remarkable progress, given the global challenges presented in 2020 due to the ongoing COVID-19 pandemic and related lockdown measures. The project, which aims to disseminate information designed to guide patients and providers, national authorities, and international bodies towards improved treatment for children with MDR-TB, has made great strides in all studies and received media coverage on multiple platforms.
During 2020, the study emblem (the dandelion) was designed to represent children’s innocence and freedom, while hinting at the movement of air, which can be challenging for many children who are affected by TB. During World TB Day in 2020, a video highlighting the scope of the BENEFIT Kids Project was released and shared on multiple platforms.
Further progress has been made in the first half of 2021 and all studies under the BENEFIT Kids umbrella have reached key milestones.
As part of Output 1, the aim is to provide improved evidence from existing data for better MDR-TB treatment for children through two systematic reviews of the MDR treatment literature in paediatrics and will feed into WHO guideline development. During 2020, the literature search for the review article on the pharmacokinetics and dosing of second-line TB drugs in children and adolescents was completed. Analyses has been postponed until after the WHO guideline discussions for the second review (see below).
For the second review on treatment outcomes, progress has been made on the literature search and the secondary analysis was initiated early 2021. Close collaboration with WHO has taken place in order to include the outcomes of the literature review in their 2021 guidelines on MDR treatment for children happening in mid-June 2021.
Output 2 of the project consists of five clinical trials to deliver improved evidence for better MDR-TB prevention and treatment for children:
-Trial 1 is called the “Delamanid Crush study”, which is led by TASK and assesses the relative bioavailability in adults of Delamanid dispersed in water compared to whole tablet form. In 2020 all approvals have been granted and the study opened to accrual in October. All study activities had been completed with the 24 participants in 2021 and by June, pharmacokinetic assay work and data analysis was underway. Study result dissemination is scheduled for the last quarter of 2021.
-Trial 2 is the “PERFORM study” (Pharmacokinetics of lEvofloxacin FORmulations in children with MDR-TB exposure) and evaluates the pharmacokinetics and acceptability of 100 mg dispersible compared to 250 mg non-dispersible tablets of levofloxacin in children exposed to MDR-TB. During 2020, World Health Organisation Research Ethics Review Committee (WHO ERC) , Health Research Ethics Committee (HREC) and South African Health Products Regulatory Authority (SAHPRA) approvals have been granted. The first patient was screened in October 2020. By June 2021, recruitment is at target with half of the children required already enrolled. It is anticipated that study activities will be completed in the last quarter of 2021.
-Trial 3 is called the “CATALYST study” (Clofazimine and moxifloxacin PK, safety, and AccepTAbiLitY for paediatric TB treatment), and is a phase I/II trial of the pharmacokinetics, safety, tolerability, and acceptability of new formulations of clofazimine and moxifloxacin in children treated for rifampicin-resistant TB. This is a multi-site study which will recruit at the DTTC Brooklyn Chest Hospital (BCH) site as well as in India (partner BJMC and JHU, PI: Dr Aarti Kinikar) and the Philippines (De la Salle Medical Centre, PI: Dr Mel Frias) University. During 2020, the three sites prepared for opening of the study and the first three participant were enrolled early 2021 in South Africa. The team also collected qualitative data from the participants.
-The “TB CHAMP” trial is the first ever randomized phase III placebo-controlled trial to assess the efficacy of levofloxacin preventive therapy vs. placebo in child contacts of MRD- TB. As of the end of 2020, 801 of 1009 children had been screened and 633 enrolled in the study. Interim analysis took place in Quarter 3 of 2020 after 500 contacts had been followed up for at least 24 weeks. By May 2021, 709 children had been enrolled in the study.
-Trial 5 is the “PETITE study” (PharmacokinEtic and safeTy of the 4-In-1 granules inneonaTEs) which is led by neonatologist Adrie Bekker. This is an open label, single arm, two-stage trial to evaluate the single and multi-dose pharmacokinetics and safety of the abacavir/lamivudine/ lopinavir/ritonavir (30/15/40/10mg) (4-in-1) fixed-dose granule formulation in HIV-exposed neonates. This study opened to accrual in September 2020 and Cohort 1A and Cohort 1B (16 children in total) was completed. The interim analysis was completed, and protocol amendment is required before Cohort 2 commences.
Output 3 aims to produce targeted formulation development and market shaping to improve availability of child-friendly formulations of key second-line TB drugs and will be undertaken in partnership with TB Alliance. Some progress has been made with identifying potential manufacturers through a Request for Proposal (RFP) process.
The BENEFIT Kids Project was also featured on multiple media platforms, including the Stellenbosch University website, newspapers, and radio broadcasts (see table below). In addition, in December 2020, Unitaid published an article on their website featuring interviews with DTTC team members Susan Purchase, Hazel Davids-Ruiters, Simphiwe Simelane, and Daphne Van Ster. The article highlighted the importance of the work being done as part of the TB CHAMP study.
Although 2020 has been a challenging year, the dedicated team as part of the BENEFIT Kids Project persevered and are on track to make real changes in the lives of children affected by MDR-TB.
In the media
- Stellenbosch University. Research project bridges treatment gap for children with MDR-TB. 24 March 2020. Available online http://www.sun.ac.za/english/Lists/news/DispForm.aspx?ID=7224
- Youtube. BENEFIT Kids: Research project bridges treatment gap for children with MDR-TB. 24 Mach 2020. Available online https://www.youtube.com/watch?v=0AvwN35R6qY
- Daily Maverick. South Africa: TB in children: Important research being done in Cape Town. 25 March 2020. Available online https://www.dailymaverick.co.za/article/2020-03-25-tb-in-children-important-research-being-done-in-cape-town/
-Spotlight. TB in children: The amazing research being done in Cape Town - Kathryn Cleary interview with Anneke Hesseling and Megan Palmer. Available online: https://www.spotlightnsp.co.za/2020/03/24/tb-in-children-the-amazing-research-being-done-in-cape-town/
-Stellenbosch University website. PETITE study searches for best treatment options for newborns exposed to HIV (Featuring Adrie Bekker and the PETITE Study). 27 November 2020. Available online: http://www.sun.ac.za/english/Lists/news/DispForm.aspx?ID=7848
-Cape Argus. Excitement over HIV drugs for children (Featuring the PETITE Study). 9 December 2020
-Yiba.co.za. PETITE study searches for best treatment options for newborns exposed to HIV. 1 December 2020. Available online: https://yiba.co.za/petite-study-searches-for-best-treatment-options-for-newborns-exposed-to-hiv/
-Anneke Hesseling was interviewed on RSG at the Woordfees in Stellenbosch. Presenter: Suzanne Paxton. Producer: Marlinée Fouché. 9 March 2020.
-Smile FM. BENEFIT Kids Project: The University of Stellenbosch is leading a new R280 million... 4 March 2020
talks@stellenboschuni. PODCAST: PETITE study searches for best treatment options for newborns exposed to HIV (Featuring the PETITE Study). 3 December 2020. Available online: https://anchor.fm/stellenbosch-university/episodes/PETITE-study-searches-for-best-treatment-options-for-newborns-exposed-to-HIV-en6qvs