Transfusion and Treatment of severe Anaemia in African Children: a randomised controlled trial (TRACT)

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

In sub-Saharan Africa severe anaemia is one of the most common reasons why children end up in hospital. It can kill children directly - and also contributes indirectly to the 800,000 child malaria deaths/year. For children hospitalised with severe anaemia (defined as a haemoglobin below 6g/dl) outcomes remain poor, with 9-10% dying in-hospital and an additional 12% dying in the 6 months following admission - and a further 6% having another episode of severe anaemia requiring additional treatment and re-hospitalisation. The high 6-month case fatality and chronic ongoing health issues of children with this condition indicate that the current recommendations and/ management strategies are not working in practice. Because severe anaemia is very common, the high 'hidden' sickness and mortality occurring after the initial diagnosis is likely to contribute to overall under-five mortality. If not adequately addressed, severe anaemia may therefore be an obstacle to achievement of the Millennium Development Goal No.4 on child survival in Africa.

The investigators in this trial include specialists in child health, infectious diseases, transfusion medicine, and anaemia research. They have considerable experience in doing large clinical trials in hospitals with limited resources in Africa. Through extensive review of the available data and literature, the group have identified key areas of severe anaemia management which need to be addressed in a clinical trial, namely
1/Which children should receive a transfusion? Current WHO guidelines, designed to avoid overuse of blood, recommend transfusions only in children with a haemoglobin (Hb) <4g/dl (or <6g/dl if accompanied by complications). These specific recommendations have not been evaluated in clinical trials and thus practice varies across African countries. We don't know if giving blood to all children with Hb <6g/dl would help. 2/ How much blood should be given in a transfusion? On current recommendations a quarter of children receiving transfusions remain severely anaemic and up to one third get two or more blood transfusions during a single hospital admission. We don't know if giving larger initial volumes of blood would help - this could also reduce risks from additional transfusion (which include bad blood matching or blood infections), and the amount of time health personnel spend getting blood ready. 3/ What, if any, longer-term support should children get after hospital admission? The major factors related to poor longer term outcome are multiple vitamin and mineral deficiencies and blood infections caused by bacteria - we don't know if giving vitamin supplements or antibiotics to prevent infections would improve outcomes.

TRACT is designed to answer these questions. It is a randomised controlled trial involving 3700 children aged 2 months to 12 years admitted to hospitals with severe anaemia in Malawi and Uganda. The trial will take place over 2 years and children will be followed up for 6 months to make sure longer-term outcomes are captured. The trial will simultaneously look at three ways management of severe anaemia might be improved - with the aim of reducing early and late deaths, and anaemia recurrence or readmission to hospital. The trial will compare (i) current conservative WHO recommendations for transfusion against a more liberal approach, in terms of who gets blood and how much blood they get (iii) additional multi-vitamin multi-mineral supplements compared with the standard folate/iron recommended by WHO and (iii) an antibiotic, cotrimoxazole, to prevent new bacterial infections for 3 months compared with no antibiotic. The design is practical with broad, largely clinical inclusion criteria, so that children can be rapidly identified and recruited at hospital admission. The interventions are practical; many are already in use for other diseases so could be implemented in under-resourced paediatric health facilities across Africa at the end of the trial.

Technical Summary

TRACT is a multicentre randomised controlled trial to identify optimal transfusion strategies and supportive treatment for 3700 African children, aged 2 months to 12 years, presenting to hospital with severe anaemia (defined as haemoglobin (Hb) <6 g/dl). Children will be enrolled at admission to hospital over 2 years in Malawi and Uganda and followed for 6 months. The trial has been designed to address the poor outcome of this condition including high rates of in-hospital mortality, 6-month case fatality and chronic morbidity. Factors associated with poor outcome include potentially treatable co-morbidities such as recurrent infection and multiple vitamin deficiencies, which are not addressed in current guidelines. TRACT is designed to probe each of these multiple contributing factors directly. TRACT will simultaneously evaluate three ways to reduce short and longer-term mortality (primary endpoint) and morbidity following severe anaemia in Sub-Saharan Africa using a factorial design:

1/ Liberal transfusion (30ml/kg) versus conservative transfusion (20ml/kg) vs no transfusion (last strategy for children with Hb>4 g/dl and uncomplicated severe anaemia only)
2/ Multi-vitamin multi-mineral (MVMM) supplementation (including folate/iron) for 3 months versus routine care (folate/iron alone)
3/ cotrimoxazole prophylaxis for 3 months versus no antibiotic prophylaxis.

The primary outcome is cumulative mortality to 4 weeks (transfusion comparisons) and to 6 months for the nutritional support/antibiotic prophylaxis comparison. Secondary outcomes include mortality at 48 hours, 4 weeks, 3 months and 6 months (cumulative) (where not the primary outcome); development of new profound anaemia (Hb<4g/dl) during acute admission or development of severe anaemia (Hb<6g/dl) post discharge; readmission to hospital; proportion achieving correction of anaemia (defined by WHO as Hb>9g/dl); adverse events relating to transfusion.

Planned Impact

Children with severe anaemia (SA) in Africa will be key beneficiaries. SA is a leading cause of morbidity, hospital admission and death in Sub-Saharan Africa, contributing to ~800,000 malaria deaths/year. Incomplete response to SA treatment results in relapse, readmission and death occurring soon after diagnosis. Current policies guiding clinical management are fragmented, based on weak evidence and often impractical. Since SA is so common the poor outcome and high 'hidden' chronic morbidity, if not adequately addressed, may be a key obstacle to achievement of Millennium Development Goal No.4 on child survival in Africa. The proposed trial will evaluate key elements of an integrated management strategy, including transfusion, in African hospitals on the basis of clinical effectiveness and costs.
In order for benefits to be realised, we plan to engage with (1) national policymakers (Ministry of Health, blood transfusion services, child health services); (2) international policymakers (WHO, UNICEF); (3) healthcare workers, nursing and paediatric associations, and NGOs involved in providing treatment or advocacy for children with severe anaemia in order to disseminate the outputs from the trial.
These stakeholders will benefit from our research, which aims to provide clear evidence on optimal treatment of children with severe anaemia, which is currently lacking. If the trial interventions reduce rates of re-admission to hospital, and are efficient and cost-effective for transfusion services, this could greatly improve overstretched acute child health and transfusion services.
In order to influence relevant policymakers and practitioners, we will also need to engage with academic audiences (who influence WHO policy), and those training health workers. Trainers of healthcare workers may benefit from new evidence from a controlled trial of what works and what does not work. Results from the trial may spur further research and academic debate, helping to catalyse further research on (cost-)effective interventions and improvement of care for children with severe anaemia in low-income settings.
Since the trial is large and pragmatic, incorporating children with both acute and acute-on-chronic anaemia, with few exclusion criteria, it will enable development of new guidelines and policy that cut across multiple 'syndromic' presentations - adopting a horizontal integrated rather than a vertical approach to management. Key enrolees will include children admitted to hospital with anaemia and malaria, sepsis, malnutrition, HIV, sickle cell disease and other conditions (eg lower respiratory tract infection). The pragmatic design is critical to translation of results to clinical practice; in malaria-endemic Africa, distinguishing between different underlying comorbidities, eg malaria and sepsis, in a severely ill child is often impossible at presentation to hospital. Since most treatment decisions are made on clinical criteria alone (or with limited diagnostic information eg malaria film and haemoglobin test), the trial results will have relevance to clinical practice and be immediately generalisable. There may be variation in response to the trial interventions and therefore the analysis plan will ensure that key syndromic groups, age groups and susceptibility (HIV or genetic factors) are considered. Whilst a single guideline is anticipated, refinement of this will be possible for particular sub-groups where response is not uniform.
The proposal will address whether the interventions represent value-for-money through a cost-effectiveness analysis (CEA) for each strategy investigated in the trial, which will draw upon existing knowledge and generate new costing data. Particular attention will be paid to blood transfusion service needs; ways in which blood can be delivered most efficiently to the benefit of the largest number of individuals (children in particular), will be explored during the trial and incorporated with trial results.

Publications

10 25 50
 
Description Major Overseas Programme Grant
Amount £45,000,000 (GBP)
Funding ID 203077/Z/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2021
 
Description Wellcome Collaborative Award in Science
Amount £3,944,185 (GBP)
Funding ID 209265/Z/17/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2018 
End 06/2022
 
Title Development of Open Clinica for multisite trial 
Description Open Clinica an open source database software that was specifically adapted for use in this trial by our programmer/data manager 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Wider appreciation that open source software can be used as a platform for GCP trial and is compliant with FDA standards 
URL http://www.ncbi.nlm.nih.gov/pubmed/21453454
 
Title Pragmatic Deferred Consent Proceedure for research in emergency medicine 
Description FEAST is the largest Phase III paediatric fluid resuscitation trial ever undertaken. To ensure an ethical and humane process to approaching parents- we developed a novel strategy for deferred consent. We were uncomfortable with full consent waiver since this may mean that parents may never get to know that their child was involved in a research study - which if they had known at the time of admission they could have exercised their right to refuse. For the sickest children we opted for, and have ethical approval for, parental verbal assent, where parents understood that their child would be involved in a clinical trial, but the details would be given after recruitment - during informed consent- once their child was stablised. We plan substudies to evaluate this with social sciences groups specializing in research ethics. Our methodology has been written up and recently submitted for publication. 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact The ethical landscape has changed so vastly such that any pragmatic consenting process giving the key sensitivities to parents so they can weigh up risks and benefits contextually is now a rare phenomenon. Having presented the FEAST trial at international paediatric critical care conferences and more recently in a meningitis meeting - our consent process was welcomed as practical and helpful example by paediatricians who are struggling with European ICH GCP legislation. There have been two important regulatory developments in recent years. Firstly, in January 2007 EU paediatric medicine regulation (Regulation (EC) No 1901/2006) requiring all new license applications to include paediatric data. Followed by the December 2006 amendment to the EU trials directive that was intended to enable research in emergencies. Recent reports suggest this is not working in practice. The new requirement for research in children is compounded by the lack of guidance for conducting studies in this setting. FEAST trial consent process therefore sets a benchmark for future paediatric trials. 
URL http://www.ncbi.nlm.nih.gov/pubmed/23408950
 
Title TRACT database 
Description Open Clinica programmed for the transfusion trial 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact Share facility for data entry in a multi centre trial 
 
Description Human Genetics 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution Basic science investigation for FEAST trial and planned investigation in TRACT trial
Collaborator Contribution Design of basic science investigation
Impact Laboratory strengthening at Mbale Regional Referral Hospital, Eastern Uganda Multi-disciplinary: medical, immunology, molecular, genetics
Start Year 2011
 
Description Mbale Clinical Research Institute, Mbale, Uganda 
Organisation Mbale Clinical Research Institute
Country Uganda 
Sector Hospitals 
PI Contribution The Wellcome Trust has funded MCRI as part of the Major Overseas Award to Oxford-Kemri Wellcome Trust Programme. The collaboration is led by Programme members working with the Director of the Mbale Clinical Research Unit. We have established a strong relationship with MCRI having supported his PhD studies and his transition from a clinical and managerial career to a research career.
Collaborator Contribution Over the last 3 years Mbale has established a track record of clinical trials, receiving subcontracts for £996k and £812k in the last 3 years (subcontracted from the £3.2M and £2.4M awards for the TRACT and COAST trials) and recent award from MRC for a Phase II study of antibiotic treatment targeting non-typhoidal salmonellae (TABS).
Impact Award of a subcontract from the KEMRI Wellcome Trust Programme for £1.5 Million in 2016. The building of a new research laboratory to strengthen diagnostic and molecular research. The will enable the centre to expand its research portfolio in future.
Start Year 2016
 
Description Mbale and Soroti Hospitals- Wellcome Trust Collaboration 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution These previously research naïve hospitals were brought into the FEAST trial by the PI working in parntership with Malaria Consortium, Uganda. The site PIs have worked with the FEAST team to develop a clinical research platform to study acute malaria, which remains the major cause of admission. Comparative studies with Kilifi offer new potential insights into disease pathogenesis.
Collaborator Contribution Development of a clinical research team and undertaken a number of substudies A new laboratory will be built in the 2104, supported by Imperial College
Impact Routine clinical surveillance is due to be introduced and already a number of sub studies of life threatening childhood infections within FEAST have provided collaborative links with the KEMRI Wellcome Trust Programme. These include studies of pathogenesis (immunology and pathogen biology groups), evaluation of community perceptions of the consent process developed for FEAST, case control genetic studies and new biomarkers for severe malaria. A number of these studies are being conducted by the PI from Mbale who is registered on KEMRI Open University PhD programme.
Start Year 2008
 
Description Mbale and Soroti Hospitals- Wellcome Trust Collaboration 
Organisation Mbale Regional Hospital
Country Uganda 
Sector Hospitals 
PI Contribution These previously research naïve hospitals were brought into the FEAST trial by the PI working in parntership with Malaria Consortium, Uganda. The site PIs have worked with the FEAST team to develop a clinical research platform to study acute malaria, which remains the major cause of admission. Comparative studies with Kilifi offer new potential insights into disease pathogenesis.
Collaborator Contribution Development of a clinical research team and undertaken a number of substudies A new laboratory will be built in the 2104, supported by Imperial College
Impact Routine clinical surveillance is due to be introduced and already a number of sub studies of life threatening childhood infections within FEAST have provided collaborative links with the KEMRI Wellcome Trust Programme. These include studies of pathogenesis (immunology and pathogen biology groups), evaluation of community perceptions of the consent process developed for FEAST, case control genetic studies and new biomarkers for severe malaria. A number of these studies are being conducted by the PI from Mbale who is registered on KEMRI Open University PhD programme.
Start Year 2008
 
Description Medical Research Council Clinical Trials Unit 
Organisation Imperial College London
Department Department of Paediatrics
Country United Kingdom 
Sector Academic/University 
PI Contribution Work leading up the trials, identification of partners, trial sites and design and execution of clinical trials
Collaborator Contribution Design of clinical trials, trial governance and data management, statatistical expertise Multidisciplinary clinical trialists, infectious disease speacialists, health economists and specialists in health policy
Impact FEAST trial Publications Alexander Fleming Award TRACT trial
Start Year 2008
 
Description Medical Research Council Clinical Trials Unit 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution Work leading up the trials, identification of partners, trial sites and design and execution of clinical trials
Collaborator Contribution Design of clinical trials, trial governance and data management, statatistical expertise Multidisciplinary clinical trialists, infectious disease speacialists, health economists and specialists in health policy
Impact FEAST trial Publications Alexander Fleming Award TRACT trial
Start Year 2008
 
Description POST and COAST trials 
Organisation The Prince Charles Hospital
Department Social Work Department
Country Australia 
Sector Hospitals 
PI Contribution Development and conduct a pilot study (POST) for the main COAST trial
Collaborator Contribution Development of the pilot study (POST) and partnership with Fischer and Paykel
Impact none realised yet
Start Year 2012
 
Description SMAART consortium 
Organisation Wellcome Trust
Department Mahidol University-Oxford Tropical Medicine Research Programme
Country Thailand 
Sector Academic/University 
PI Contribution The main aim of SMAART is to conduct better research studies faster, to improve outcomes from severe malaria. SMAART will act as the operational platform by which future research is planned in a coordinated and reciprocal manner to continuously update disease definitions and treatment guidelines for severe malaria.
Collaborator Contribution To overcome the barriers to achieving this goal, SMAART brings together applicants and co-investigators from three Wellcome Trust major overseas programmes (KEMRI Wellcome Trust Programme, Kenya, Malawi-Liverpool-Wellcome Trust Unit, Malawi (Prof David Lalloo) and Mahidol Oxford Research Unit, Thailand together with African scientists from existing or new collaborations and specialists in clinical trials ( MRC CTU at UCL) and ultimately national and international stakeholders. All are necessary to ensure that the most important questions are identified and combined optimally in the most efficient trial design which is acceptable and relevant to parents, healthcare professionals, ethical review boards and ministries of health. The network is thus a multi-disciplinary team providing complementary expertise and added value including links to other networks. The SMAART consortium encompasses decades of clinical and academic experience, track records of successful high quality research in low-income settings, and significant impact as evidenced by publication citation, grant funding and policy change.
Impact none yet; meeting planned for June 2016 to plan the grant submission to UK funder collaborative award
Start Year 2015
 
Description SMAART consortium 
Organisation Wellcome Trust
Department Malawi-Liverpool Wellcome Trust Clinical Research Programme
Country Malawi 
Sector Charity/Non Profit 
PI Contribution The main aim of SMAART is to conduct better research studies faster, to improve outcomes from severe malaria. SMAART will act as the operational platform by which future research is planned in a coordinated and reciprocal manner to continuously update disease definitions and treatment guidelines for severe malaria.
Collaborator Contribution To overcome the barriers to achieving this goal, SMAART brings together applicants and co-investigators from three Wellcome Trust major overseas programmes (KEMRI Wellcome Trust Programme, Kenya, Malawi-Liverpool-Wellcome Trust Unit, Malawi (Prof David Lalloo) and Mahidol Oxford Research Unit, Thailand together with African scientists from existing or new collaborations and specialists in clinical trials ( MRC CTU at UCL) and ultimately national and international stakeholders. All are necessary to ensure that the most important questions are identified and combined optimally in the most efficient trial design which is acceptable and relevant to parents, healthcare professionals, ethical review boards and ministries of health. The network is thus a multi-disciplinary team providing complementary expertise and added value including links to other networks. The SMAART consortium encompasses decades of clinical and academic experience, track records of successful high quality research in low-income settings, and significant impact as evidenced by publication citation, grant funding and policy change.
Impact none yet; meeting planned for June 2016 to plan the grant submission to UK funder collaborative award
Start Year 2015
 
Description Targeting Anti-microbiological treatment in African children with Severe Malaria (TABS) 
Organisation Cipla
Country India 
Sector Private 
PI Contribution Development of early phase trial of antimicrobial treatment- submitted to EDCTP and now to submit to MRC
Collaborator Contribution Development of study protocol Industry Donations of product for free (Azithromycin and placebo) and/or diagnostics
Impact Submission to EDCTP- not funded Preparation of grant for 2013
Start Year 2012
 
Description Targeting Anti-microbiological treatment in African children with Severe Malaria (TABS) 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Public 
PI Contribution Development of early phase trial of antimicrobial treatment- submitted to EDCTP and now to submit to MRC
Collaborator Contribution Development of study protocol Industry Donations of product for free (Azithromycin and placebo) and/or diagnostics
Impact Submission to EDCTP- not funded Preparation of grant for 2013
Start Year 2012
 
Description Targeting Anti-microbiological treatment in African children with Severe Malaria (TABS) 
Organisation Radboud University Nijmegen
Department Department of Pharmacology and Toxicology
Country Netherlands 
Sector Academic/University 
PI Contribution Development of early phase trial of antimicrobial treatment- submitted to EDCTP and now to submit to MRC
Collaborator Contribution Development of study protocol Industry Donations of product for free (Azithromycin and placebo) and/or diagnostics
Impact Submission to EDCTP- not funded Preparation of grant for 2013
Start Year 2012
 
Description Targeting Anti-microbiological treatment in African children with Severe Malaria (TABS) 
Organisation Spectral Diagnostics Inc
Country Canada 
Sector Private 
PI Contribution Development of early phase trial of antimicrobial treatment- submitted to EDCTP and now to submit to MRC
Collaborator Contribution Development of study protocol Industry Donations of product for free (Azithromycin and placebo) and/or diagnostics
Impact Submission to EDCTP- not funded Preparation of grant for 2013
Start Year 2012
 
Description Uganda Blood Transfusion 
Organisation Imperial College London
Department Department of Paediatrics
Country United Kingdom 
Sector Academic/University 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description Uganda Blood Transfusion 
Organisation Medical Research Council (MRC)
Department MRC Clinical Trials Unit
Country United Kingdom 
Sector Public 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description Uganda Blood Transfusion 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description Uganda Blood Transfusion 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Multiple 
PI Contribution For the purposes of the FEAST and TRACT trial developed new network of clinical trial sites
Collaborator Contribution Blood transfusion services will be critical in this collaboration for the successful conduct of the transfusion componant of the TRACT trial
Impact TRACT trial protocol approval in Uganda Trial started enrolment in Sept 2013
Start Year 2013
 
Description BBC World News Transfusion trial 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Increased awareness the children are the chief recipients of all donated blood in sub Saharan Africa- most give as emergency treatments

Emphasized importance of research/clinical in the area of emergency treatment since most treatments given in the emergency room have not been tested in clinical trials

Transfusion trial was designed to determine which children with severe anaemia would benefit from a blood transfusion (short and long-term) and which children did not require a transfusion (thus reducing the demand on the blood transfusion services
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/news/world-africa-33925701
 
Description Interviewed by Voice of America about NEJM Severe Malaria Perspective 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact New England Journal Perspective on Severe Malaria in African Children: need for continuing investment. I discussed the slow pace of progress in clinical trials in Africa; yet 10% of children with severe malaria will die. In the drive to eliminate malaria most scientists and policy makers felt that malaria was all but conquered. Many expressed surprise at the burden of disease. Thought published only on 22nd December 2016 the current Altmetrics for this article is 124.
Year(s) Of Engagement Activity 2017
URL http://www.voanews.com/a/death-toll-from-malaria-among-african-children-called-unacceptably-high/366...
 
Description Training of new DMC members 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Finding new members with experience to populate Data Monitoring Committee is very hard. In Africa few statisticians involved in trials have been members of DMC. In the TRACT trial we have invited two junior statisticians to act as observers during DMC meetings - for training and experience

none yet
Year(s) Of Engagement Activity 2014