Therapeutic Approaches to Malnutrition Enteropathy
Condition: Severe Acute Malnutrition
MeSH terms: Malnutrition; Severe Acute Malnutrition
Study type: Interventional
Phase: Phase 2

Summary: 
      The TAME study will evaluate four new approaches which will be compared against the standard
      care currently in use in the treatment of malnutrition enteropathy in children with severe
      acute malnutrition. A high pathogen burden causes damage to the intestinal mucosa which
      exacerbates nutritional impairment and leads to further susceptibility to infection and
      impaired epithelial regeneration. Enteropathy is characterised by multiple epithelial
      breaches, microbial translocation from gut lumen to systemic circulation and systemic
      inflammation.The trial will evaluate the potential impact of four interventions (colostrum,
      N-acetyl glucosamine, teduglutide, and budesonide) given for 14 days, which aim at mucosal
      restoration. The trial will determine if repairing damage to the small intestinal mucosa
      leads to the reduction of systemic inflammation and thus lessening the nutritional
      impairment, and so if this contributes to the reduction of mortality in children.

      In Zambia only, endoscopic biopsies and confocal laser endomicroscopy will be used to
      evaluate response and confirm safety at a mucosal level.

      Identifying an agent or agents which contribute most to mucosal healing will then ultimately
      lead to further large phase 3 trial in which the agent(s) will be further evaluated.

      The trial also anticipates to gain a more in depth understanding of pathophysiology and may
      identify where current management strategies of treating malnutrition enteropathy in children
      are failing.
    

Detailed description: 
      Over the last two decades, three key developments in the approach to treatment have improved
      the outcome of SAM: standardised management protocols, ready to use therapeutic food (RUTF),
      and community management of acute malnutrition (CMAM). CMAM has four components, namely,
      community mobilization and community identification of cases of acute malnutrition,
      supplementary feeding programme (SFP) for children with moderate acute malnutrition (MAM),
      outpatient therapeutic programme (OTP) of SAM with no medical complications and inpatient
      management of SAM with medical complications However, severely malnourished children with
      medical complications requiring hospitalisation often fail to respond to treatment, and
      continue to experience high inpatient mortality of up to 35%. Even after discharge, children
      have a poor prognosis, with 42% mortality over the subsequent year. It is a subgroup of
      children with SAM and acute or persistent diarrhoea who pose the most difficult management
      challenges, although the vast majority of children with SAM have substantial degree of
      enteropathy. Current treatment guidelines for SAM are not well supported by an evidence base,
      and there is a dearth of clinical trial data; in particular, there are no specific
      interventions to target enteropathy in SAM. In a systematic review, only three trials were
      found which inform management of SAM and persistent diarrhoea, and no trials dealing with the
      HIV-infected child. The investigators therefore believe that novel therapeutic approaches are
      urgently needed, and that a series of small phase 2 trials could guide development of a new
      generation of treatments. These trials should focus on repairing damage to the small
      intestinal mucosa, as there is now substantial evidence that this plays a central role in the
      genesis of systemic inflammation, bacterial translocation and sepsis with all its adverse
      nutritional consequences.

      Evidence of malnutrition enteropathy: Recent studies have been highly informative about the
      infectious contribution to dysfunction of the small intestine in malnourished children. A
      high pathogen burden causes damage to the mucosa which exacerbates nutritional impairment and
      leads to further susceptibility to infection and impaired epithelial regeneration, in a
      cyclical process first described in Central America in the 1970s. This mucosal damage in SAM
      is here referred to as malnutrition enteropathy. In previous studies, markers of microbial
      translocation and systemic inflammation were dramatically increased in children with SAM
      compared to healthy controls. Enteropathy is characterised by multiple epithelial breaches,
      microbial translocation from the gut lumen to the systemic circulation, and systemic
      inflammation. Epithelial breaches were present in histological (haematoxylin/eosin-stained)
      sections and sections studies using immunofluorescence for claudin 4 and E-cadherin. In
      adults, these lesions were shown to occur in vivo using confocal laser endomicroscopy. There
      was also a consistent pattern of blunted epithelial repair, with reduced glucagon-like
      peptide 2 (GLP2) in serum, reduced trefoil factor 3 in duodenal aspirates, and a strong
      transcriptomic signature of impaired mucosal defence. Two further immunological abnormalities
      were identified in children with malnutrition enteropathy: low-level false positive
      coeliac-like autoantibodies, and upregulation of SMAD7 similar to the pattern seen in Crohn's
      disease. Together, these abnormalities indicate there is substantial structural and
      functional damage to the small intestine, and that this primary gut pathology is associated
      with systemic sequelae.

      WHO guidelines clearly state that antibiotic treatment should be part of the initial
      management of all cases of SAM, whether associated with overt features of infection
      ('complicated' SAM) or not ('uncomplicated' SAM). Antibiotic use was associated with reduced
      short term mortality and improved nutritional rehabilitation in SAM with no medical
      complications in Malawi but post-discharge prophylaxis with cotrimoxazole did not reduce
      long-term mortality following complicated SAM in Kenya, and in Niger antibiotics conferred no
      benefit. Even in the best outcome group in the Malawi antibiotic trial, mortality was not
      reduced below 4% over 12 weeks in children managed as outpatients in OTP. This seems to be a
      glass floor below which it has never been possible to reduce mortality in SAM, even in
      uncomplicated cases in the community or in clinical trials. In SAM with medical complications
      who are managed as inpatients, mortality is much higher, and when combined with HIV infection
      can reach 35% in hospital and 62% over one year post-discharge.

      If optimal antibiotics are insufficient to reduce mortality below 4% in uncomplicated cases
      treated in the community, and mortality is much higher in complicated cases, there must be
      other factors which lead inexorably to adverse outcomes in a subgroup of children with
      complicated SAM. It seems that a major contributor to the residual mortality observed after
      current optimal therapies have been implemented is failure of restitution in the gut. This
      means that in a subset of children with SAM, largely but not exclusively those with
      persistent diarrhoea, the intestinal mucosa is damaged and leaky, permitting efflux of plasma
      proteins and influx of luminal microbial products, and fails to repair following the
      infective insult. The evidence leading to this interpretation is:

      i. In children with SAM and persistent diarrhoea, there are epithelial gaps visualised in
      haematoxylin/eosin-stained sections and using immunohistochemistry for claudin-4 and
      E-cadherin; ii. These are morphologically similar to lesions seen in environmental
      enteropathy in adults, though more severe and more numerous; iii. Plasma proteins are easily
      detected in western blots of duodenal aspirates, suggesting leakage from blood to gut lumen;
      iv. Biomarkers of microbial products (bacterial DNA and lipopolysaccharide) are found in very
      high concentrations in peripheral blood, direct evidence of microbial translocation from
      lumen to blood; v. Children with persistent diarrhoea and malnutrition have reduced
      circulating concentrations of glucagon-like peptide-2 (GLP2) and reduced trefoil factor 3 in
      intestinal secretions, suggesting a failure of homeostatic repair mechanisms. Circulating LPS
      was inversely proportional to circulating GLP2, and this remained true in multivariate
      analysis.

      In a recent study of children with complicated SAM in Malawi, children who died were more
      likely to have diarrhoea and higher levels of faecal calprotectin (a marker of intestinal
      inflammation), and levels of systemic inflammation were directly related to mortality. There
      is now clear evidence that enteropathy is associated with systemic inflammation and mortality
      in SAM and a new treatment paradigm is required to improve outcomes.

      There is a need for new approaches. The investigators postulate that the central lesion in
      malnutrition enteropathy is epithelial leakiness through tight junction damage and
      microerosions, and so propose therapy directed at restoration of the mucosal barrier which
      will permit reversal of the cascade of downstream inflammatory derangements. Novel approaches
      are required in order to achieve a radical improvement in outcome, and reduce current
      unacceptably high mortality rates. The TAME trial will investigate four potential therapeutic
      approaches to achieving mucosal restoration. Colostrum, teduglutide and N-acetyl glucosamine
      are all intended to achieve mucosal healing. Budesonide, a corticosteroid with limited
      absorption, is targeted at the downstream inflammatory changes; in inflammatory conditions
      such as coeliac disease or Crohn's disease, steroids produce rapid clinical response. If any
      of these interventions impact on malnutrition enteropathy, it will become possible to trial
      these novel therapeutic approaches in phase 3 trials to detect an impact on our world's most
      disadvantaged children. The trial will also generate useful information about
      pathophysiology.

      The novel therapeutic approaches to be tested in the TAME trial are:

        -  Colostrum: high-protein bovine colostrum powder (Neovite) orally 1.5 g every 8 hours for
           14 days, reconstituted with water and given through a nasogastric (NG) tube or orally.
           Colostrum reduces the increased epithelial permeability seen in heat shock. Colostrum
           contains nutrients, immunoglobulins and growth factors, including epidermal growth
           factor (EGF) and insulin-like growth factor 1 (IGF-1).

        -  N-acetyl glucosamine (GlcNAc) will be given orally or via NG tube for 14 days, gradually
           increased from a starting dose of 0.5g, to 1g three times daily to avoid osmotic
           diarrhoea. Impaired glycosylation of glycosaminoglycans has been noted in oedematous
           malnutrition, with reduced concentrations of glycosaminoglycans found in blood, urine,
           kidney, brain and small intestine. Specific consequences of reduced heparan sulphate
           expression include gut epithelial leakiness with hypoalbuminaemia. GlcNAc administration
           has been demonstrated to restore the intestinal epithelial charged barrier in Crohn's
           disease. GlcNAc may theoretically induce osmotic diarrhoea if not absorbed in the small
           intestine. Although this has not been observed clinically in animals or in older
           children we will use a dose escalation schedule to minimise the chance of this.

        -  Teduglutide by subcutaneous injection (0.05mg/kg/day) daily for 14 days. Teduglutide is
           a long-acting form of GLP2 which has proven efficacy in intestinal failure, improving
           absorption and reducing the need for parenteral support. GLP2 is a hormone secreted by L
           cells in the terminal ileum, which drives epithelial repair and mediates intestinal
           adaptation by increased cellular proliferation and villus hypertrophy.

        -  Budesonide 3mg orally daily for 7 days, then 2mg for 4 days then 1mg for 3 days.
           Budesonide is standard therapy for Crohn's disease, and can be used for refractory
           coeliac disease. Since malnutrition enteropathy is characterized by intestinal
           inflammation, with infiltration of activated T cells, an anti-inflammatory approach is
           rational. A prior trial of mesalazine in Kenya confirmed an immuno-modulatory approach
           is safe in the setting of SAM, but targeting the small, rather than large, intestine
           with a more potent agent is likely to be more effective.
    

Intervention name(s): Colostrum high protein powder (Neovite); N-Acetyl Glucosamine (GInNAC); Teduglutide; Budesonide
Intervention type(s): Dietary Supplement; Drug; Drug; Drug
Intervention description(s): Bovine colostrum provided as powder will be reconstituted and administered orally or via NG tube.; N-Acetyl glucosamine provided as powder will be reconstituted and administered orally or via NG tube.; Teduglutide will be administered daily as subcutaneous injection; Budesonide liquid (as marketed for nebulisation) will be administered orally or bia NG tube daily.
Intervention MeSH terms: Budesonide; Teduglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment