Novel therapeutic approaches to malnutrition enteropathy

Severe acute malnutrition (SAM) is often complicated by infection and metabolic derangements, and in this situation it becomes a medical emergency with appreciable mortality (up to 35%, depending on the nature of the complications, over one month). Although early, protocol-based management in the community can bring the mortality down to 4%, this is still unacceptable for a benign disorder affecting many hundreds of thousands of the world's children. One of the most difficult management problems is SAM complicated by persistent diarrhoea, indicative of an intestinal derangement we refer to as malnutrition enteropathy. We know, from previous and current work, that malnutrition enteropathy is a failure of the barrier function of the intestine - its ability to absorb nutrients while simultaneously excluding the bacteria which inhabit the gut from the moment of birth. Under the microscope this barrier failure appears as gaps in the epithelium - the lining cell layer of the intestine - and it allows microbial components into the bloodstream where they generate an inflammatory response. This process is called microbial translocation and we have evidence that it is one of the critical disturbances leading to deterioration and death in children with SAM. If we can identify treatments to heal this barrier failure we may be able to interrupt the fundamental derangements of malnutrition enteropathy and save many thousand of lives, particularly in Africa and South Asia.

We propose to test out five novel treatments in an attempt to heal malnutrition enteropathy. If these are successful in reversing the laboratory abnormalities we have identified in children with SAM, we will go on and carry out a large-scale multi-centre clinical trial to measure any reduction in mortality in several countries. We will also have demonstrated the usefulness of novel strategies for repairing the barrier failure which characterises other disorders common in Europe and North America, such as inflammatory bowel disease and a sort of infectious disorder common in patients in critical care units.

We will test the first four interventions - bovine colostrum, N-acetyl glucosamine, teduglutide and budesonide - against standard care by randomising suitable children with SAM and persistent diarrhoea in Zambia and Zimbabwe. The most promising of these will then be evaluated against a treatment which we already know has some impact in this condition - elemental feeding - in a more intensive study designed to provide very detailed confirmation of safety and healing ability in the intestine.

Once the two parts of this study are complete, we hope to have a candidate treatment for further testing, as well as detailed information on its activity which will enable us to test it across the world in the most rigorous medical scientific trial format. We will also generate large amounts of scientific data to help us to understand better the pathways of damage, which is essential in case the interventions work less well than we hope.

The team we have assembled draws on years of experience of malnutrition enteropathy and the interventions we propose to evaluate, and will establish a scientific consortium in the UK and southern Africa dedicated to reducing the impact of this neglected but important disorder. Capacity development in Africa is an integral part of our strategy, and we have deep experience of this in both countries. We are also fully conversant of the ethical and regulatory requirements of such work, as we are currently engaged in non-therapeutic studies in the same groups of children. Ethical issues have been considered fully in the preparation of this proposal and are set out in detail.

The persistently high mortality of complicated severe acute malnutrition (SAM) is unacceptable for a so-called benign condition. While community management of SAM achieves historically low mortality rates in uncomplicated cases, our hospital practice confronts us daily with the reality of the most severe and complicated cases, for which current management algorithms are inadequate. One central pathophysiological derangement is malnutrition enteropathy, which is characterised by epithelial barrier breakdown and associated with very high levels of microbial translocation and systemic inflammatory responses. Children with SAM and malnutrition enteropathy often, but we suspect not always, have persistent diarrhoea. It is this group of children we propose to recruit into two consecutive parallel group randomised phase 2 trials. In the first part, eligible children will be randomised to one of four novel interventions or to standard care, and evaluated by the response primarily of non-invasive biomarkers and secondarily of simple clinical indices of response (diarrhoea volumes, appetite and play, weight gain). These interventions are bovine colostrum, N-acetyl glucosamine, teduglutide and budesonide. In the second part, the most promising intervention will be compared against exclusive elemental feeding using an amino acid-based tube feed. In the second part, endoscopic biopsies and confocal laser endomicroscopy will be used to evaluate response and confirm safety at a mucosal level.

The objective of the study as a whole is to identify an agent or agents which can contribute significantly to mucosal healing. The agent(s) will then be further evaluated in a large multi-centre phase 3 trial, well powered to detect reduced mortality as a primary endpoint. We anticipate that the success of this phase 2 trial will be apparent not just in terms of therapeutic progress but in enhanced understanding of pathophysiology.

Children with SAM complicated by diarrhoea - a group with very high mortality - will be the immediate beneficiaries of this work. The hypothesis underlying the whole body of work proposed here is that healing the mucosal defects which underlie barrier impairment can be healed with one or more of five novel interventions. As malnutrition enteropathy seems to confer such high mortality in children with SAM, we aim to reduce that mortality through mucosal healing. In the phase 3 trial which we hope will result from the work we propose here, we will aim for a 20% reduction in mortality with whatever intervention (or combination) seems most promising.

We will engage WHO and UNICEF as soon as the trial results are clear, so that we obtain their engagement in the design and conduct of the phase 3 trial(s) which we intend to conduct. Other key stakeholders in the community of scientists interested in SAM and its management work elsewhere in Africa and in South Asia, and several key scientists are based in North America. Results will be disseminated in Zambia, to the Commonwealth Association for Paediatric Gastroenterology and Nutrition, and to paediatric societies meetings in the UK and USA. If these interventions look promising we will want to design the most robust trial possible, almost certainly multi-centre involving centres in Africa and South Asia, and this will require collaboration across investigators involved in recent initiatives funded by the Gates Foundation (in which Kelly and Amadi are involved) and MRC.

UK taxpayers, who will have funded this work if this proposal is accepted, will benefit through the support for UK scientists in this global health endeavour, and will have supported work on a disorder which commands a great deal of public sympathy and good will, in countries with which the UK has strong historic ties. The results will be published in British journals, amongst others and at UK scientific meetings. Furthermore, the engagement we have with the Centre of the Cell at Barts & The London will afford an opportunity for UK students to learn about this disorder and explore an important facet of global health.

African scientists will gain from this, not just through the delivery of work on a major public health problem, but also through training and skills development and international collaboration. We envisage that this work will support one PhD student in Lusaka, and we will look for opportunities to engage masters students in these studies also. This strategy has worked well in the past; the applicants have facilitated career development of more than 20 African scientists through similar research projects.