A phase III cluster randomised placebo-controlled trial to assess the efficacy of preventive therapy in child and adolescent contacts of MDR-TB

Lead Research Organisation: Stellenbosch University
Department Name: Dept of Paediatrics and Child Health

Abstract

Context of research: To become sick with tuberculosis (TB), someone must first be exposed to someone who is coughing, become infected and then develop the disease. People with HIV and young children are more likely to develop TB disease once they are infected. One way to prevent TB is to find the people who live in a home with someone who has TB, check them and treat those with TB infection. This will prevent them from getting sick with TB disease. Many studies have shown that a drug called isoniazid (INH) reduces the risk of developing TB when given after being coughed on, so World Health Organization (WHO) advises giving INH to HIV-infected people and children under age 6 for six months when they have contact with someone with TB.

Right now it is unclear what medicine we should give a child who has been exposed to someone with multidrug-resistant (MDR)-TB, when the germ is resistant to the most commonly used TB medicines, like INH. MDR-TB is becoming more common. The WHO estimated that there were more than half a million cases worldwide in 2012. Worldwide, it is estimated that at least a million children are exposed to MDR-TB every year. With new tests to diagnose TB quickly that can also detect resistance to the common TB medicines, the number of adults who are diagnosed with MDR-TB cases is increasing. In turn, the number of children exposed to MDR-TB is also increasing.

Treating children who become sick with MDR-TB takes a long time (usually 18 months), usually needs a hospital stay, has medicines that may have many side effects, and is expensive. For these reasons, preventing MDR-TB in children is therefore very important.

Until now, there have been no big and well designed studies to help us decide if using medicine to prevent a child with contact with someone with MDR-TB from becoming sick works. A few studies where doctors treated patients who have been in contact with MDR-TB have been done, but, each of them had problems. We think medicine to prevent MDR-TB might work, but a better type of study, a randomised control trial, needs to be done to prove that it works before we can be sure.
Aims and objectives: We want to do a study in South Africa that looks at people living in the homes of someone with MDR TB disease. We will use a drug that doctors already use to treat MDR-TB called levofloxacin (LFX). We will test whether this medicine, given every day for 6 months, can prevent children from getting TB and/or dying. We will include children who live with someone with MDR-TB in the study. Children who get the medicine will be compared to those who get a sugar pill or placebo. This sugar pill looks like LFX but has no active medicine. Children will be followed for 24 months to make sure they do not get TB or have any side effects. We will also check if the medicine was easy to take, if it was safe, or if the TB became resistant to the LFX. We will also check how expensive it is to give this kind of medicine in the way that we think it should be given. Some children and their families will be asked to talk about their experience of the study and the medicine with the clinic staff.
Potential applications and benefits: Until doctors learn what treatments work for preventing MDR-TB in children, it will hard to tell families what to do. If the medicine we are testing works to prevent MDR-TB, and is safe, and acceptable to families, we will be able to tell other doctors how to decrease MDR-TB all over the world. TB programmes will also benefit from this research because fewer children will get a disease which is costly to treat. Most importantly, if this medicine works, this study could greatly benefit children exposed to MDR-TB.

Technical Summary

Overview: TB-CHAMP is a multi-centre, phase III double blinded, parallel group, placebo-controlled cluster randomised superiority trial of levofloxacin (LFX) for the treatment of high-risk HIV-infected and -uninfected child and adolescent household contacts of adult MDR-TB cases.
Objectives: The trial will address the following questions: Is LFX (intervention arm), given daily for 6 months, effective in the prevention of MDR-TB and/or all-cause mortality in high-risk child and adolescent household contacts of MDR-TB cases? Other questions are: a) Does LFX have acceptable toxicity and tolerability in children? b) Is adherence similar between the study arms? c) Is there an increase in LFX resistance in children on LFX developing incident TB? d) Is LFX prophylaxis for child and adolescent contacts of MDR-TB cases cost-effective and acceptable?
Design: The trial will be community-based using a household contact tracing strategy. Children will be randomised to: 1) LFX (~15-20 mg/kg, maximum 750mg), once daily 7 days/week or 2) LFX placebo, once daily, 7 days/week. Drug will be given as scored dispersible tablets, dosed using weight-bands. The trial will include 24 months of enrolment, and 24 months of study follow-up (total duration 48 months). Children will be screened for TB at entry and excluded if diseased. Children with the highest risk of progression to TB will be enrolled.
Outcomes: The primary outcome is incident TB disease or death due to any cause by 24 months post-randomisation. Secondary outcome measures include: Adverse events equal or greater than grade 3; Adherence over 6 months; TB-disease free survival over 12 months; TB-disease over 24 months; Incidence of LFX resistance in children developing incident TB; Cost-effectiveness of the LFX regimen; Acceptability of the LFX regimen. Nested economic and qualitative feasibility studies will evaluate the cost, impact and acceptability of the preventive strategy.

Planned Impact

Who will benefit from this research and how? Results will benefit national and international TB programmes, the WHO, the Global Drug Facility and Fund, NGOs, and most importantly, high-risk child contacts of MDR-TB: young children, children & adolescents with HIV infection, and their families.
Policymakers: The lack of evidence on MDR-TB preventive therapy makes it difficult to develop evidence-based guidelines, leading to 'recommendations' based on opinion only. If proven to be efficacious, safe, cost-effective, and acceptable to families and the NTP, we anticipate that this trial will inform global guidelines for post-exposure preventive therapy in child and adolescent contacts of MDR-TB. With secondary end points evaluating TB disease free survival over 12 months, we will demonstrate how much MDR-TB disease can be prevented with shorter follow-up. This will further reduce the cost of MDR-TB prevention than the current WHO-recommended 24 months follow-up.
Ministries of Health and TB programmes: Given the difficulties in treatment, including frequent toxicities, prolonged hospitalizations and high cost to health systems, the successful implementation of MDR-TB prevention in children is likely to be highly cost-effective. If we show that the preventive therapy regimen averts the development of MDR-TB disease in children following exposure, it will dramatically reduce the current costs of treating children. It will also reduce the number of health centre visits required, the number of investigations conducted and will limit the expensive (and long-term) complications of MDR-TB disease and its treatment, including serious and often irreversible toxicities such as hearing loss (occurring in up to 20% children) due to injectable drugs.
Program implementation: We plan to include qualitative research to address questions regarding healthcare workers' perception of our MDR-TB preventive treatment strategy. The use of simple weight band tables for the trial will simplify paediatric MDR-TB prevention, and make it easier for healthcare workers to provide the correct drug dosages to children.
MDR-TB-exposed children and their caregivers: Globally, a million children are potentially exposed to MDR-TB each year. Young and HIV-infected children are at high risk of progressing to disease following exposure to M.tb. While treatment outcomes for children with MDR-TB are good with individualised therapy, the treatment is long and frequently causes significant adverse events. We will assess families' and children's perspectives of the MDR-TB preventive therapy and will investigate adherence and acceptability of drug formulations in children and their caregivers.
Communities where the incidence of MDR-TB is high: If it is found that MDR-TB in children and vulnerable adolescents can be prevented by an already available, safe and affordable TB drug, the limited financial and human resources used to manage children with MDR-TB could efficiently used to treat patients with other TB conditions. Within the communities that the trial will be conducted there will be significant capacity building due to improved infrastructure, health systems and staff training.
Pharmaceutical companies: If successful, we anticipate widespread support for the development and use of a paediatric LFX formulation for MDR-TB prevention and treatment. The timing of these benefits will depend on WHO and NTPs treatment guidelines revisions. The involvement of WHO and the South African NTP in the trial is anticipated to increase the speed of uptake.

Publications

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Furin J (2015) A bitter pill to swallow: the need for better medications for drug-resistant tuberculosis in children. in The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

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Garcia-Prats AJ (2015) Pharmacokinetics and Safety of Ofloxacin in Children with Drug-Resistant Tuberculosis. in Antimicrobial agents and chemotherapy

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Garcia-Prats AJ (2016) Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children. in The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

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Gumbo T (2016) Partnerships to Design Novel Regimens to Treat Childhood Tuberculosis, Sui Generis: The Road Ahead. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Harausz EP (2017) New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations. in American journal of respiratory and critical care medicine

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Harausz EP (2017) Stability of Second-Line Tuberculosis Medications Mixed With Milk or Yogurt. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

 
Title Study logo 
Description We have, in partnership with local community groups, developed a study logo for TB-CHAMP. It uses a sports theme, with a child boxing. 
Type Of Art Image 
Year Produced 2015 
Impact Improved visibility of the study and communication with internal and external stakeholders 
 
Guideline Title WHO Essential Medicines List
Description Paediatric formulation development of levofloxacin for TB CHAMP and data from the TB CHAMP PK lead in study has influenced decision for Global Drug Facility (GDF) to make this formulation available in >50 countries through a grant mechanism. This formulation is also now on the WHO's Essential Medicines List and has undegone WHO prequalification
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
 
Description Participation in WHO MDR-TB guideline meeting
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
URL http://www.who.int
 
Description Post-exposure management of multidrug-resistant tuberculosis contacts: evidence-based recommendations. Policy Brief
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
URL http://sentinel-project.org/wp-content/uploads/2015/11/Harvard-Policy-Brief_revised-10Nov2015.pdf
 
Description Rapid WHO guidance on use of bedaquiline and delamanid in adults and children
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Children will now for the first time formally be allowed access delamanid for MDR-TB treatment, down to age 6 years. Data on bedaquiline are still pending. The implications are that children can now access safer and more child friendly regimens (i.e without injectable drugs like amikacin being mandatory in the MDR-TB treatment regimen).
URL http://www.who.int
 
Description WHO guidelines on MDR-TB management in adults and children
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Children with MDR-TB may now also benefit fro shorter treatment regimens, along with the option of not having to receive injectable TB drugs, which have considerable toxicity (25% of children develop hearing loss on these drugs). Professor Hesseling and Dr. Seddon participated in this international guideline process.
URL http://www.who.int
 
Description BMRC Fellowship
Amount £263,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2018 
End 12/2022
 
Description Fellowship
Amount € 60,000 (EUR)
Organisation Spanish National Research Council (CSIC) 
Sector Public
Country European Union (EU)
Start 10/2017 
End 03/2019
 
Description Harry Crossly Foundation
Amount R 70,000 (ZAR)
Organisation Harry Crossley Foundation 
Start 12/2017 
 
Description NHLS
Amount R 76,000 (ZAR)
Organisation National Health Laboratory Services, South Africa 
Sector Public
Country South Africa
Start 10/2017 
End 09/2019
 
Description NHLS, South Africa
Amount R 100,000 (ZAR)
Organisation National Health Laboratory Services, South Africa 
Sector Public
Country South Africa
Start 10/2017 
End 09/2019
 
Description Strategic Health Innovation Partnerships (SHIP)
Amount R 5,000,000 (ZAR)
Organisation Medical Research Council of South Africa (MRC) 
Sector Public
Country South Africa
Start 09/2015 
End 08/2018
 
Title Data forms, study questionnaires, standard operating procedures 
Description All case report forms (CRFs) and data capturing tools and other study documentation have been developed by the clinical team at DTTC with input from the other participating South African sites and CTU and have been transferred to MRC CTU at UCL for database development, where the CTU will be using the Cactus platform. Database development is expected to be completed by mid-April, when DTTC will pilot the database and provide final feedback to MRC CTU. Site training will be provided face to face during the first week of May with all 3 sites in Cape Town for face to face protocol, database and other training. The study manual of operations (MOP) is in draft format and will be completed during March 2017, with input from other sites. 
Type Of Material Improvements to research infrastructure 
Year Produced 2016 
Provided To Others? Yes  
Impact Inout was solicited from our South African collaborative sites to jointly develop the most robust and relevant data capture tools and systems, along with rigorous and feasible randomization and pharmacy plans, general study guidance, in close collaboration with MCR CTU at UCL. All database development for substudy work (e.g. the PK lead in study, biomarker, microbiome and health economics studies, are completed internally at DTTC and have been established already, along with a robust open source sample management platform. 
URL http://www.sun.ac.za/tb
 
Title Data on the palatability of a novel paediatric levofloxacin formulation in children: 
Description We conducted a study on the palatability of a novel paediatric levofloxacin formulation in children. Our findings indicated that 14/15 (93%) caregivers indicated that the preparation of doses was easy or very easy. All reported that the tablet dissolved easily. 11/13 (85%) caregivers felt the taste of the new formulation was equivalent or better/much better than the adult 250 levofloxacin formulation while 11/15 (73%) caregivers were happy with the total reconstituted drug administration volume - typically 5ml (Purchase, in progress). Also presented as an abstract at the 48th Union Meeting in Mexico, 2017 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2017 
Provided To Others? Yes  
Impact This study provided practical guidance for caregivers and health providers regarding the administration of the novel paediatric formulation we had developed for use in this trial. This formulation will now become globally available, and will thus have broad impact and utility beyond our trial. The manuscript is in progress. 
URL http://guadalajara.worldlunghealth.org
 
Title International consensus case definition for paediatric TB diagnostic studies 
Description The PI contributed to the development and publication of the updated NIH case definitions for use in paediatric TB diagnostic research. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact Standardization of case definitions for diagnostic studies in clinical research in paediatrics will advance the field significantly, enabling improved quality and reporting of individual studies, while enhancing comparison across different studies 
URL http://www.ncbi.nlm.nih.gov/pubmed/26409281
 
Title Manual of operations 
Description Manual of operations (including standard operating procedures) to guide trial implementation 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact None yet but is anticipated to improve standardised data collection within the TB-CHAMP trial and across other trials 
 
Title New clinical research field offices established 
Description We have developed 2 new community-based trial sites in the Cape Town Metropolitan area, to serve trial participants. The first is in Khayelitsha (Tanbo Road clinic) and the second in Mitchell's Plain Health sub districts (Beautiful Gate). These sites were developed given the community-based nature of this trial and the high burden of MDR-TB in these communities.Both sites are fully set up with appropriate patient examination room, sample processing/storage, medical equipment and infection control measures are in place. ON-site data entry is also in place, to improve efficiencies with data management. Both sites have internet and telephone connectivity. 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? No  
Impact This improved research infrastructure will support appropriate recruitment, retention and clinical care for our trial participants and their families. 
 
Title Pharmacokinetic study of novel trial paediatric levofloxacin formulation: PK lead in study 
Description Given the challenges of dosing young children with adult formulations, we supported the development of a novel dispersible 100mg scored levofloxacin formulation in children (Macleods Pharma Limited, Mumbai, India). The levofloxacin model developed from this data was used to analyse the levofloxacin paediatric PK data on the novel paediatric 250 mg formulation developed for the TB-CHAMP PK lead-in study. Data were compared to our previously developed paediatric levofloxacin population PK model (See Denti et al, 2017). To inform TB-CHAMP study implementation and practical dosing of study drug in young children, we completed a lead-in study of the PK, acceptability and palatability of this novel dispersible formulation in children <5 years of age, exposed to MDR-TB. Levofloxacin 15-20mg was administered once daily by caregivers to children for 7-14 days. Tablets were administered whole, crushed or dissolved in water. A questionnaire was administered to 15 caregivers on the last day of levofloxacin administration. In brief, following intensive PK sampling (6 time points), data from 24 children (144 samples) dosed with the new dispersible tablet were compared with the prediction from the model derived above. An estimation of the difference in the bioavailability was completed for the novel formulation, while maintaining other model parameters as constant. Re-estimation of the PK parameters of the model was completed for the original cohort study. Figure 1 shows substantially higher exposures with the novel dispersible formulation in children, which was mostly due to improved bioavailability of this formulation (Garcia-Prats, in progress)_. Shaded areas are where the model predicts/expects the various percentiles of the data to fall. Lines are the percentiles of the data). No AEs occurred in this sample of 24 children. The safety and efficacy of this dispersible formulation will be systematically evaluated in the TB CHAMP trial. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2017 
Provided To Others? Yes  
Impact These data indicate substantially higher exposures of levofloxacin using the novel dispersible trial formulation and has informed the more conservative dosing guidance for levofloxacin using this formulation in our trial, and also for routine clinical use (e.g. through in -country procurement through the Global Drug Facility and WHO). The manuscript is in progress. 
 
Title Pharmacometric model of levofloxacin in children 
Description Pharmacometric model data on the pharmacokinetics of levofloxacin in children:There are limited paediatric data on levofloxacin pharmacokinetics (PK). Using data from an ongoing observational cohort study, we characterized the PK and safety of the existing 250mg adult levofloxacin formulation (15 vs. 20mg/kg daily) in children <15 years receiving MDR-TB treatment. Children underwent intensive sampling at 6 time points after an exact 15 or 20mg/kg levofloxacin dose. PK parameters were calculated using non-linear mixed effects modelling. Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption. Allometric scaling improved the model fit, and age-driven maturation of clearance (CL) reached 50% at 2 months of age. Levofloxacin exposures were substantially lower than in adults receiving a similar mg/kg dose (1000mg), 45 vs. 129 mg·h/L, and more closely approximated adult exposures after a 500mg dose. Safety analyses included 70 children, median age 2.1 years (range 0.4-7.3 years). Total person-time of observation was 68.5 years (median 11.6 months; IQR 9.2-14.7 months). Adverse events were mostly mild (grade 1/2), with no arthritis events and only 3 grade 1 arthralgia events in 3 children (event rate 0.044 events/person-year). Of 8 grade 3/4 adverse events, only 1 was possibly related to levofloxacin (grade 3 headache). No adverse events resulted in permanent levofloxacin discontinuation (Denti,2018). 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2017 
Provided To Others? Yes  
Impact This model has informed the more appropriate dosing of levofloxacin in children affected by TB. See our publication (Denti et al, 2017, AAC) 
 
Title Standardized paediatric TB case definitions for contact investigation studies 
Description The protocol team developed rigorous yet pragmatic standard case definitions for prevalent and incident TB in child household contacts of MDR-TB for clinical research, to facilitate trial entry point classification. This process involved extensive international consultation. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact This standardized approached to case definitions of TB disease in active surveillance (household contact studies) has already been shared with 2 other research groups and has been incorporated into 2 other trial protocols (V-QUIN, VietNam), and Phoenix (multisite international trial). This data sharing and harmonization of key study methods will enable rigorous end point evaluation and cross-trial comparison. 
 
Title Study case report forms 
Description Standard case report forms have been developed and have been harmonised with other MDR-TB prevention trials. This will enhance both the internal quality of the trial and improve combined data analysis across different trials. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2015 
Provided To Others? Yes  
Impact Improved communication and collaboration between different research groups engaged with MDR-TB trials 
 
Title Pharmacometric model to inform paediatric levofloxacin dosing in children for MDR-TB prevention 
Description Population Pharmacokinetics of Levofloxacin in children: The fluoroquinolone levofloxacin is the levo-isomer of ofloxacin and is widely used for prevention and treatment of MDR-TB. Limited data on its PK is available in children. The aim of this study is to characterise levofloxacin PK in children to optimise dosing. Methods: We developed a model in collaboration with the University of Cape Town Clinical Pharmacology Division (Paolo Denti, Helen McIlleron). In brief, 109 South African children, median age 2.1 years (range 0.3-8.7) and weight 12 kg (6-22), received daily levofloxacin within a study on MDR-TB treatment/prophylaxis. Samples were collected before dosing and at 1, 2, 4, 6, and 8 hours post-dose. Children received 15 or 20 mg/kg, with exact dosing on the day of PK sampling. Smaller children received crushed tablets, often using a nasogastric tube. NONMEM 7.3 with FOCE-I was used to interpret the PK data. The effect of body size was captured with allometric scaling [1], while the effect of age, HIV status, treatment vs. prophylaxis, and drug administration procedure were evaluated. Simulations from the final model were used to optimise doses across different weight bands, targeting adult exposure. Results Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption through transit compartments [2]. After inclusion of allometric scaling, which substantially improved the fit, the model could characterise age-driven maturation of CL with an effect reaching 50% around 2 months after birth. CL in a 12 kg, 2-year-old child was estimated 4.7 L/h. The use of nasogastric tube increased the rate of absorption, but no significant effect on bioavailability could be detected. HIV positive children were found to have 16% slower CL. Levofloxacin exposures in this cohort of children were significantly lower than previously reported in adults dosed 1000 mg daily (a similar mg/kg dose): 45 vs. 129 mg·h/L [3]. Only part of this difference could be explained by allometric scaling. To achieve exposures similar to adults a dose of 50 mg/kg would be required, with smaller children receiving higher mg/kg doses, except very young children with immature CL (<1 year old). Conclusion Consistent with reports in other paediatric populations [4], children achieve levofloxacin exposures considerably lower than adults using the same mg/kg dose, and this difference cannot be fully explained by allometric scaling. Our report of slightly higher exposure in HIV positive children would need further investigation in other studies. 
Type Of Material Computer model/algorithm 
Year Produced 2015 
Provided To Others? Yes  
Impact This model has informed the dose selection of levofloxacin for our trial and has already informed ongoing other clinical research and care. 
 
Title Trial database development 
Description The full clinical trial database has now been developed by MRC CTU at UCL 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact The trial database will allow for appropriate conduct of the clinical trial and will provide an excellent platform for future trials 
 
Description Biomarker Immunology work 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution Developed joint grant funding applications for the BMRC fellowship (James Seddon) and the Wellcome Trust (James Seddon) to complete collaborative biomarker work nested in the main TB CHAMP trial.
Collaborator Contribution Extensive grant writing, training in biomarker work, exploring of new collaboration, bio-informatics training and grant applications to support this work and join the clinical TB CHAMP team in South Africa (Dr. James Seddon)
Impact No funding yet but 2 grants pending
Start Year 2016
 
Description Biomarker sub study work 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Biomarker sample collection has started for the trial. Analysis plans and lab work flow is being planned The data collection plan has been compiled and cost parameters have been identified
Collaborator Contribution Lab work flow set up; sample storage for future use ongoing. Postgraduate students identified.
Impact Work ongoing
Start Year 2017
 
Description Biomarker sub study work 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution Biomarker sample collection has started for the trial. Analysis plans and lab work flow is being planned The data collection plan has been compiled and cost parameters have been identified
Collaborator Contribution Lab work flow set up; sample storage for future use ongoing. Postgraduate students identified.
Impact Work ongoing
Start Year 2017
 
Description Microbiome work 
Organisation National Health Laboratory Services, South Africa
Country South Africa 
Sector Public 
PI Contribution Joint development of stool and respiratory biome sub studies which will support 1 masters and 1 PhD lab student supervised by Professor Andrew Whitelaw. Sub study protocol developed for implementation at the Cape Town site only (DTTC). This work will also be expanded to investigate the effect of levofloxacin on general antimicrobial resistance at a population level.
Collaborator Contribution Development of lab protocols, SOPs and funding of lab consumables, student supervision.
Impact 1 new Masters and 1 new PhD student will be enrolled during 2017 under supervision of Professor Andrew Whitelaw, NHLS and Chair: Medical Microbiology services. Students will be supported by NHLS and South African scholarships (e.g. SA NRF)
Start Year 2016
 
Description Study product development 
Organisation Macleods Pharmaceuticals Ltd
Country India 
Sector Private 
PI Contribution We have established a strategic partnership with an Indian generic drug company, McCleods, to develop a paediatric levofloxacin formulation (and matching placebo) for child participants in TB-CHAMP. A formal contract was finalised between Stellenbosch University and McCleods in 2015. This strategic collaboration was facilitated by TB Alliance, through its close partnership with DTTC. Specifications for the formulation, based on our pharmacokinetic research, and modelling work were established and the research team worked intensively to inform the development of the new formulation and guide regulatory dossiers required for in-country regulatory submissions in South Africa (South African Medicines Control Council; MCC) and local ethics committees. Update for most recent reporting period: Study product and drug shipment Study product of the active 100 mg paediatric levofloxacin formulation is on site and is currently being evaluated in the PK lead in study. We are awaiting shipment of the 100 mg placebo formulation from India. We in addition have also secured an adult 250 mg levofloxacin formulation from McCleods, with matching placebo, in order to accommodate older children who may prefer the adult tablet to higher number of paediatric dispersible formulation. As a contingency plan, if McCleods fails to deliver on the paediatric 100 mg placebo formulation on time, the trial will open with the 250 mg levofloxacin (currently used routinely to treated MDR-TB disease in children in South Africa), and we will include the paediatric formulation later, as it becomes available. The contract to McCleods is milestone driven and further disbursement of funds is dependent on delivery of acceptable trial product and matching placebo. The pharmacy plan will be finalised in March 2017, based on the above considerations.
Collaborator Contribution A 100 mg scored dispersible formulation has been developed; a limited bio-equivalence study has been completed in adults. A full investigational medicinal product dossier has been developed by McCleods for MCC submission in South Africa. 20% of the total drug development costs has been transferred as per mutual agreement and packaging, labelling and import is being finalized. This is the first ever paediatric dispersible tablet developed. It is envisaged that data from our trial will support in-country drug registration and eventually, marketing and wide -spread access. The first batch of study product will be delivered prior to trial startup. Also see above for the additional 250 mg formulation and matching placebo, which is already available. Product labelling is much simpler for this formulation (tablets in a plastic container) compared to the paediatric formulation, which comes in blister packs.
Impact Study product (paediatric levofloxacin formulation) and matching placebo, 100 mg scored dispersible tablets as well as 250 mg active and placebo tablets
Start Year 2015
 
Description TB-CHAMP Economic Evaluation 
Organisation University of Stellenbosch
Department Department of Economics
PI Contribution The clinical and social science team has worked with the economics team to define study questions, gather data for parameter input, develop models and collected data in the field (clinical, epidemiological and costing data)
Collaborator Contribution The team, which includes an economist, health economist and PhD student has drafted the Budget impact analysis (BIA) and cost effectiveness analysis (CIA) protocols - The data collection plan has been compiled and cost parameters have been identified - The team is finalising the decision tree for the Markov model and the QALY assessment tools for children Ongoing quality of life assessment work is planned
Impact Capacity Building (PhD Support - Economics Evaluation Team: Martina Mchenga) was supported by TB-CHAMP to attend the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) South African Chapter Congress on 19 and 20 September 2016 (Midrand). The aim of the conference was the development of Health Technology Assessment. The conference offered training, where she learnt how to construct and implement decision tree and Markov models in TreeAge pro. Economic evaluation studies were also presented to show the real life application of the models. This was an opportunity for Martina to learn from other experts in the field. In April, 2017, Martina will attend the 2017 Society for Research in Child Development (SRCD) biennial meeting in Austin, Texas. This is a forum where researchers interested in child development research meet and share ideas on the topic. It is another opportunity for Martina to learn and also create networks for potential future collaboration. Through the TB-Champ PhD program Martina is also benefiting from the mentorship from Ronelle Burger and Thomas Wilkinson via face-to-face meetings as well as email and skype interaction. Martina is learning advanced modelling in Excel for decision modelling
Start Year 2016
 
Description TB-CHAMP Economic Evaluation 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution The clinical and social science team has worked with the economics team to define study questions, gather data for parameter input, develop models and collected data in the field (clinical, epidemiological and costing data)
Collaborator Contribution The team, which includes an economist, health economist and PhD student has drafted the Budget impact analysis (BIA) and cost effectiveness analysis (CIA) protocols - The data collection plan has been compiled and cost parameters have been identified - The team is finalising the decision tree for the Markov model and the QALY assessment tools for children Ongoing quality of life assessment work is planned
Impact Capacity Building (PhD Support - Economics Evaluation Team: Martina Mchenga) was supported by TB-CHAMP to attend the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) South African Chapter Congress on 19 and 20 September 2016 (Midrand). The aim of the conference was the development of Health Technology Assessment. The conference offered training, where she learnt how to construct and implement decision tree and Markov models in TreeAge pro. Economic evaluation studies were also presented to show the real life application of the models. This was an opportunity for Martina to learn from other experts in the field. In April, 2017, Martina will attend the 2017 Society for Research in Child Development (SRCD) biennial meeting in Austin, Texas. This is a forum where researchers interested in child development research meet and share ideas on the topic. It is another opportunity for Martina to learn and also create networks for potential future collaboration. Through the TB-Champ PhD program Martina is also benefiting from the mentorship from Ronelle Burger and Thomas Wilkinson via face-to-face meetings as well as email and skype interaction. Martina is learning advanced modelling in Excel for decision modelling
Start Year 2016
 
Description Trial support and management 
Organisation University College London
Department Comprehensive Clinical Trials Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution SU has entered into a contractual agreement with the British Medical Research Council CTU (Di Gibb) to support trial implementation. This collaboration builds on previous and ongoing partnership between the Desmond Tutu TB Centre and the CTU.
Collaborator Contribution The MRC CTU will provide trial oversight, management and statistical analysis. Data development, data management, randomization, overall site management, communications and statistical analysis will be centrally managed for the 4 sites.
Impact Scope of work, contract and budget have been established
Start Year 2015
 
Description Viral pathogen co-infection studies 
Organisation University of Stellenbosch
Country South Africa 
Sector Academic/University 
PI Contribution • Sample collection has started and will be stored for future analysis The team is drafting SOPs on sample analysis
Collaborator Contribution Lab processes are being developed including SOPs and work flow; analytic plans are being developed and postgraduate students identified
Impact Work only recently initiated; sample collection has started and sample are used for future analysis
Start Year 2017
 
Title Levofloxacin paediatric formulation 
Description A 100 mg scored dispersible formulation has been developed; a limited bio-equivalence study has been completed in adults. A full investigational medicinal product dossier has been developed by McCleods for MCC submission in South Africa. paediatric dispersible tablet developed. It is envisaged that data from our trial will support in-country drug registration and eventually, marketing and wide -spread access. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact This trial product is anticipated to also be licensed and marketed in South Africa and elsewhere, for the treatment and prevention of MDR-TB in children. Currently, children with MDR-TB (disease) routinely receive levofloxacin, but using the unchildfriendly adult formulation which is not palatable, dispersible or scored 
 
Title Pharmacokinetic lead in study: novel paediatric levofloxacin formulation 
Description TB CHAMP PK lead-in Study: The clinical aspect of our trial trial has now formally opened up to clinical enrolment with the planned pharmacokinetic and acceptability study opening up in Q1 2017, to evaluate the pharmacokinetics and bio-availability of the novel 100mg dispersible levofloxacin trial formulation in the TB-CHAMP target population. We are also conducting in-depth palatability and acceptability work, and are planning on supporting an additional Masters degree student from the DTTC social science team, Lelethu Busakwe, to conduct in-depth qualitative work. Rationale and description The lack of child-friendly formulations of anti-TB medications has been a major barrier to both clinical care and research in prevention of TB in children. In order to address this challenge for TB CHAMP, a child-friendly, taste-masked and dispersible 100mg levofloxacin formulation was developed by Macleod's Pharmaceuticals Ltdm and supported by the trial. The pharmacokinetics of levofloxacin in children receiving prevention or treatment for drug-resistant TB have been evaluated in in an observational study (MDRPK1, PI Hesseling) in Cape Town, South Africa, using existing adult tablet 250 mg tablet formulations. Formal analyses has been completed and a population PK model has been developed with Dr. Paolo Denti, UCT. However, witht he exception of the adult bio-equivalence study done in India in 12 healthy adult volunteers, there is not data available on the novel levofloxacin formulation developed for this trial in children 0-5 years, our trial population. Thus we have begun an intensive pharmacokinetics and safety study of the 100mg dispersible levofloxacin trial formulation in the TB CHAMP target population, before randomisation stars, in order to ensure appropriate weight-banded dosing and exposures of levofloxacin in children in our trial. Data from this PK lead-in study will be compared to data we have on n=106 children aged 0-7 years, from our observational paediatric MDR PK 1 study (NIH-funded), using the 250 mg adult tablet formulation. To characterize the pharmacokinetics of the novel 100 mg paediatric levofloxacin scored tablets (Macleod's Pharmaceuticals Ltd.) in children 0-5 years of age, and to assess palatability and acceptability of this formulation in children and their caregivers Methods 24 children (household contacts of an adult with MDR TB, as per main TB-CHAMP trial eligibility criteria) are enrolled, in representative age strata, with enrichment in younger ages (0-2 years, where most variability is typically observed for TB drug exposures). The study opened in January 2017. Children are given the trial levofloxacin trial formulation for 7 days and discontinue the trial formulation after completion of PK sampling, and are then referred for routine local standard of care tour specialist paediatric MDR-TB clinic at Tygberberg Hospital. Children are receiving the levofloxacin 100mg dispersible tablet trial formulation once-daily at the weight-banded doses proposed for the main trial. Children undergoing PK sampling at steady state, using a semi-intensive sampling approach incljding 6 samples over 12 hours. Drug assays are completed (1 single batch) at the University of Cape Town, Division of Clinical Pharmacology. Pharmacometric modeling will be completed by Dr. Paolo Denti, University of Cape Town, Division of Clinical Pharmacology, Pharmacometric Research group, building on the existing levofloxacin population PK model (manuscript in preparation). The palatability and acceptability of the formulation (to both children and caregivers) is being studied by a Social Science team, led by Graeme Hoddinott, using questionnaires as well as unstructured in-depth interviews. There have been no serious or related drug adverse events this far; accrual will be completed in March/April 2017. Summary statistics for PK Lead-in study (children 0-5 years) Total pre-screened: n= 41 Consented and enrolled : n=14 Screened/baseline visit completed: n=13 Screened out (XDR exposure): n= 2 PK visit completed : n= 10 All study visits completed: n= 9 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact See under trial rationale for PK study above 
URL http://www.macleodspharma.com/
 
Title Population pharmacometric model of levofloxacin in children 
Description We characterized the PK of 250mg adult levofloxacin formulation (15 vs. 20mg/kg daily) in children <15 years receiving MDR-TB treatment. Children underwent intensive sampling at 6 time points after an exact 15 or 20mg/kg levofloxacin dose. PK parameters were calculated using non-linear mixed effects modelling. Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption. Allometric scaling improved the model fit, and age-driven maturation of clearance (CL) reached 50% at 2 months of age. Levofloxacin exposures were substantially lower than in adults receiving a similar mg/kg dose (1000mg), 45 vs. 129 mg·h/L, and more closely approximated adult exposures after a 500mg dose. Safety analyses included 70 children, median age 2.1 years (range 0.4-7.3 years). Total person-time of observation was 68.5 years (median 11.6 months; IQR 9.2-14.7 months). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2017
Development Status Closed
Impact This PK model has formed the basis for updated dosing guidance for levofloxacin in children affected by TB (see Denti et al, AAC, 2017) 
 
Title Field-based EDC system 
Description We will use field-based electronic data capture systems (EDC) on mobile devices, using tables or smartphones, as an innovative approach to record data for clinical studies. This approach has been developed for other large trial at our research centre (e.g. PopArt HPTN 071 trial) and will increase the quality of data quality while decreasing the time to get a final clean dataset. 
Type Of Technology Webtool/Application 
Year Produced 2016 
Impact The use o fEDC in the field will reduce data capture errors, and time to data entry. Data are also regularly available for study monitoring and interim analysis. We will work with our central trial support partners at MRC CTU, who will do database development and overall central trial data managements for the 4 sites. 
 
Title paediatric CXR central review web application 
Description We have developed robust simple tools for CXR evaluation for clinical TB trials in children and have developed an in-house webb ap to allow for uploading, central expert reviewing and data sharing of paediatric CXR images for TB trials 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2017 
Impact This application is used in TB-CHAMP, and also in SHINE (a phase 3 trial efficacy trial of TB shortening trial in children It will also be used in other large international trials (served to be provided by our group at the Desmond Tutu TB Centre, Stellenbosch University) 
 
Description Community advisory board consultations 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Community advisory board (CAB) consultations have been convened in Cape Town, South Africa (DTTC) and in Pietermaritzburg (THINK)
Year(s) Of Engagement Activity 2016
 
Description Formative social science work and community consultation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Study participants or study members
Results and Impact Material Name
Formative/Feasibility evaluation at two sites (DTTC; THINK)
Material Type
Social science research
Description
The evaluation included a range of mixed data sources: (i) review of routine summary statistics on demography, epidemiology, and health service delivery at each health facility, (ii) day long semi-structured in situ observations - completed in 10 of 16 health facilities and surrounding catchment areas, (iii) in-depth interviews with different cadres of health workers including nurses, counsellors, and community-based support staff - n = 14, (iv) group discussions with grassroots community advisory structures - n = 13, and (v) ethnographic interviews with 7 current MDR TB patients and their families - only at the THINK site. These data were collected between May and July 2016.
Provided to others
Yes
Year first provided
2016
Impact Description
The evaluation was instrumental in characterising the capacity, community acceptability, and operational platforms for delivering the trial at these two sites. It further served to characterise key issues in patient perceptions, understandings, motivations, and anxieties about participation. These insights have been summarised into 16 clinic-community narrative reports and one summary report for the study implementation team. The data will be further analysed for academic publication.
Community Advisory Board - DTTC
Presentation
30-40
Local
Carers and patient groups; community level stakeholders and researcher
Study team from DTTC
2016
DTTC hosts an institutional community advisory board (CAB). The CAB meets monthly to consult on study design operationalisation and to receive study updates in an oversight capacity- among other business. The TB-CHAMP trial protocol as well as formative/feasibility evaluation plan was presented. Routine consultation is ongoing.
The CAB supported the intent and implementation plan for the trial. Further, the CAB provided useful insight into how to explain conceptually complex concepts such as prophylaxis, drug resistance, and placebo in language that is locally appropriate.
Year(s) Of Engagement Activity 2016
 
Description Global consultation on paediatric tuberculosis disease estimates 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Dr. James Seddon participated in a global consultation convened by the WHO, on improved global estimates of the paediatric tuberculosis, in Geneva, 31 March-2 April 2015
Year(s) Of Engagement Activity 2015
 
Description Institutional CAB consultation 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Formal consultation with the DTTC Community Advisory Board to guide trial implementation in Cape Town.These consultations were highly instructive in characterising local perceptions about paediatric MDR TB and building trust and local support for the implementation of the trial at this site. Overall, there was strong support for the implementation of the trial.
Year(s) Of Engagement Activity 2012,2017
 
Description Local health department consultation: TB programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Consultation with local TB control programmes to prepare for trial implementation, including selection of TB clinics, preferred models of partnership, capacity development needs from health services and updates on trial timelines
Year(s) Of Engagement Activity 2014,2016
 
Description MDR-TB in children 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Dr. James Seddon was invited to present a lecture on tuberculosis in children, with a special emphasis on MDR-TB, on World TB Day, World TB Day, 24 March 2015, at the London School of Hygiene and Tropical Medicine, London (invited speaker)
Year(s) Of Engagement Activity 2015
 
Description Presentation of pharmacokinetic lead in study results: TB CHAMP, 48th World Lung Health meeting, Mexico (peer-reviewed) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of pharmacokinetic lead-in study findings: acceptability and palatability of paediatric levofloxacin tablets in children
Our findings show that the novel 100 mg paediatric formulation we had developed for this trial, was overall, well tolerated, acceptable and highly preferable compared to the traditional adult formulation. Oral presentation, Dr. Sue Purchase, trial clinician, at the 48th Union World Lung Health Conference, Guadelajara, Mexico
Year(s) Of Engagement Activity 2012,2017
URL http://guadalajara.worldlunghealth.org
 
Description Scientific presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A. Hesseling, PI, presented the study rationale and methods at the "Imbizo" community TB education/outreach platform, at the 46th IUATLD (Union) meeting in Cape Town, November 2016
Year(s) Of Engagement Activity 2015
URL http://capetown.worldlunghealth.org/programme/imbizo
 
Description Scientific presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented trial rationale and methods to audience of >100 participants at the Paediatric MDR-TB symposium (speaker: Hesseling) as well as at the WHO Childhood TB Subgroup meeting.
Year(s) Of Engagement Activity 2015
URL http://capetown.worldlunghealth.org/programme
 
Description Scientific symposium (peer reviewed) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Scientific symposium held at 48th Union Meeting, Mexico 12-14 October 2017.Convened by A. C. Hesseling. Title of symposium: The evolving landcape of MDR-TB trials in children
Year(s) Of Engagement Activity 2012,2017
URL http://guadalajara.worldlunghealth.org