Reformulated F75 Milk to Treat Severe Acute Malnutrition
Condition: Malnutrition; Diarrhoea; Metabolic Disturbance
MeSH terms: Malnutrition; Severe Acute Malnutrition; Diarrhea
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Inpatient treatment for complicated severe acute malnutrition (SAM) continues to have a high
      mortality in Africa. This is partly because children are commonly brought for admission
      because they are seriously ill, rather than being brought to hospital because of malnutrition
      alone. Mortality rates are especially high where SAM is complicated by HIV or TB. The early
      phase of inpatient nutritional treatment for severe acute malnutrition is based on a
      low-protein milk known as F75, which is given to improve metabolic homeostasis prior to the
      re-feeding to achieve catch-up growth. F75 provides a high proportion of energy from
      carbohydrates, including sucrose, lactose and maltodextrin. However, malabsorption of
      different types of carbohydrates, but lactose in particular, is known to occur in SAM and may
      lead to osmotic diarrhoea. Diarrhoea is common in children with SAM and is associated with
      increased mortality. Furthermore, switching from a catabolic state to a high energy diet that
      consists of predominantly carbohydrates can lead to 're-feeding syndrome' that may lead to
      severe electrolyte abnormalities and multiple organ dysfunction.

      The aim of this trial is to determine whether reducing the carbohydrate content of F75, and
      removing lactose, improves the stabilisation of severely malnourished children. The trial
      will involve randomising children who are eligible to receive F75 milk to either the current
      formulation or a revised formulation. Both formulations will be given according to current
      recommendations regarding frequency of feeding and caloric value. Since the purpose of F75 is
      to stabilise the child metabolically and biochemically, the primary endpoint of the trial
      will be time to stabilisation (the end of the first phase of treatment for severe acute
      malnutrition). Blood and stool samples at admission and after three days will be used to
      determine the effects on carbohydrate and fat malabsorption and evidence of the re-feeding
      syndrome. Children will be followed up until discharge from hospital. The project has been
      planned in consultation with the World Health Organisation (WHO) and, if the revised
      formulation of F75 results in improved outcomes, will lead to a global change in
      recommendations for its formulation.
    

Detailed description: 
      Admission to hospital with complicated severe acute malnutrition (SAM) in Africa commonly has
      a case fatality of 10-30%. Importantly, children are usually admitted to hospital because
      they are severely ill rather than for malnutrition alone. Mortality may be improved to some
      extent by adherence to WHO recommended management, but the direct application of these
      guidelines to all contexts is controversial. The WHO guidelines were designed on the basis of
      historical data on nutrient requirements and medical treatments and almost none of the
      recommendations are supported by evidence from clinical trials.

      For the treatment of complicated inpatient SAM, the guidelines consist of three distinct
      phases of treatment: phase 1 or stabilization phase where a low protein, liquid diet (F75) is
      introduced with a reduced energy intake (80-100 kcal/kg/day). Once a child has stabilised,
      there is a 'transition phase' consisting of either ready to use therapeutic foods (RUTF) with
      supplemental F75 or alternatively another milk formula known as F100. RUTF is a peanut based,
      energy dense supplement used to obtain catch-up growth. F100 is a liquid formula with a
      higher energy density and protein content than F75. The caloric intake is increased daily to
      a maximum of 130 kcal/kg/day. Finally, 'Phase 3' is the recovery phase during which the aim
      is to achieve catch-up growth with either RUTF or F100.

      Typically, the highest mortality rate is found in the early phases of treatment. Children who
      fail treatment early often have profuse diarrhoea, signs of circulatory insufficiency which
      is hard to treat. The most recent reports from Zambia and Kenya note a prevalence of
      diarrhoea of more than 60% amongst children with SAM and it is associated with increased
      mortality. Currently at Kilifi County Hospital and Coast Provincial General Hospital, ~20% of
      children are given either a diluted or lactose-free milk feed during rehabilitation of SAM,
      although there are no specific guidelines for this. Diarrhoea may be caused by a viral or
      bacterial gastroenteritis, sepsis, or may be nutritionally induced (osmotic). There are no
      routinely available tests to distinguish osmotic from infective or other causes of diarrhoea
      in hospitals in sub-Saharan Africa.

      The proportion of energy derived from carbohydrates in F75 is high. The carbohydrates in F75
      milk (as well as F100 and RUTF) consist of a mixture of maltodextrin, sucrose and lactose.
      Disaccharides such as maltose, lactose or sucrose are normally hydrolysed into
      monosaccharides by disaccharidases localized at the tip of small intestinal villi. The
      monosaccharides such as glucose and galactose can then be transported across the apical
      membrane through Na+ dependent glucose transporter, whilst fructose makes use of a
      facilitative fructose transporter. There is limited information on the intestinal function
      and intestinal carbohydrate absorption in malnourished children. However, data from Jamaica
      and South Africa suggest that there is impaired absorption of disaccharides (lactose and
      sucrose), regardless of the presence or suspicion of gastroenteritis. Limited histological
      evidence has shown intestinal atrophy in children with SAM. These data are consistent with
      clinical signs of lactose malabsorption found in children with severe malnutrition. Recently,
      evidence of impaired absorption of monosaccharide glucose in children with SAM was reported
      in Malawi.

      Apart from diarrhoea, early deterioration may also be related to severe metabolic
      derangements due to a sudden change from a catabolic to an anabolic state, resulting in
      refeeding syndrome. Refeeding syndrome is characterized by hypophosphataemia, hypokalaemia,
      hypomagnesaemia and sodium retention. These severe electrolyte disturbances can lead to
      impaired cardiac, pulmonary and neurological function and are often hard to treat. By
      receiving energy predominantly from sugars, pancreatic insulin secretion is increased which
      induces uptake of electrolytes including phosphate and potassium, into cells. Furthermore, as
      protein synthesis is stimulated, increased production of adenosine tri-phosphate (ATP) leads
      to a higher cellular demand for phosphate. Although insulin secretion appears to be partially
      impaired in the early stages of refeeding, hypophosphatemia is a common feature during
      refeeding of malnourished children, and is associated with mortality.

      In this trial, the investigators aim to evaluate the outcome of using a revised formulation
      of F75 milk with reduced carbohydrate composition and without lactose, compared to the
      current formulation of F75 during the initial stabilisation period amongst children with
      severe acute malnutrition. In the new formulation, more will be provided by lipids and the
      total energy provided will be unchanged. The trial will be undertaken in two hospitals in
      Kenya and one hospital in Malawi.

      Enrolment and follow up was completed in December 2015, laboratory analysis of plasma and
      faecal samples in ongoing.
    

Intervention name(s): Standard F75 Milk; Modified F75 Milk
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): This is the standard F75 milk used worldwide (Control group); This is the experimental group
Other intervention name(s): Standard formulation F75 therapeutic milk; Modified formulation F75 Milk
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: severe acute malnutrition; wasting; kwashiorkor; nutrition; feeding; milk