<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02246296</url>
  </required_header>
  <id_info>
    <org_study_id>OXTREC 58-14</org_study_id>
    <secondary_id>P.03/14/1540</secondary_id>
    <secondary_id>SSC 2799</secondary_id>
    <nct_id>NCT02246296</nct_id>
  </id_info>
  <brief_title>Reformulated F75 Milk to Treat Severe Acute Malnutrition</brief_title>
  <acronym>F75</acronym>
  <official_title>Randomized Controlled Trial of a Reduced Carbohydrate Formulation of F75 Therapeutic Milk Among Children With Severe Acute Malnutrition</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>KEMRI-Wellcome Trust Collaborative Research Program</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kamuzu University of Health Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Hospital for Sick Children</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Groningen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Oxford</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Inpatient treatment for complicated severe acute malnutrition (SAM) continues to have a high&#xD;
      mortality in Africa. This is partly because children are commonly brought for admission&#xD;
      because they are seriously ill, rather than being brought to hospital because of malnutrition&#xD;
      alone. Mortality rates are especially high where SAM is complicated by HIV or TB. The early&#xD;
      phase of inpatient nutritional treatment for severe acute malnutrition is based on a&#xD;
      low-protein milk known as F75, which is given to improve metabolic homeostasis prior to the&#xD;
      re-feeding to achieve catch-up growth. F75 provides a high proportion of energy from&#xD;
      carbohydrates, including sucrose, lactose and maltodextrin. However, malabsorption of&#xD;
      different types of carbohydrates, but lactose in particular, is known to occur in SAM and may&#xD;
      lead to osmotic diarrhoea. Diarrhoea is common in children with SAM and is associated with&#xD;
      increased mortality. Furthermore, switching from a catabolic state to a high energy diet that&#xD;
      consists of predominantly carbohydrates can lead to 're-feeding syndrome' that may lead to&#xD;
      severe electrolyte abnormalities and multiple organ dysfunction.&#xD;
&#xD;
      The aim of this trial is to determine whether reducing the carbohydrate content of F75, and&#xD;
      removing lactose, improves the stabilisation of severely malnourished children. The trial&#xD;
      will involve randomising children who are eligible to receive F75 milk to either the current&#xD;
      formulation or a revised formulation. Both formulations will be given according to current&#xD;
      recommendations regarding frequency of feeding and caloric value. Since the purpose of F75 is&#xD;
      to stabilise the child metabolically and biochemically, the primary endpoint of the trial&#xD;
      will be time to stabilisation (the end of the first phase of treatment for severe acute&#xD;
      malnutrition). Blood and stool samples at admission and after three days will be used to&#xD;
      determine the effects on carbohydrate and fat malabsorption and evidence of the re-feeding&#xD;
      syndrome. Children will be followed up until discharge from hospital. The project has been&#xD;
      planned in consultation with the World Health Organisation (WHO) and, if the revised&#xD;
      formulation of F75 results in improved outcomes, will lead to a global change in&#xD;
      recommendations for its formulation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Admission to hospital with complicated severe acute malnutrition (SAM) in Africa commonly has&#xD;
      a case fatality of 10-30%. Importantly, children are usually admitted to hospital because&#xD;
      they are severely ill rather than for malnutrition alone. Mortality may be improved to some&#xD;
      extent by adherence to WHO recommended management, but the direct application of these&#xD;
      guidelines to all contexts is controversial. The WHO guidelines were designed on the basis of&#xD;
      historical data on nutrient requirements and medical treatments and almost none of the&#xD;
      recommendations are supported by evidence from clinical trials.&#xD;
&#xD;
      For the treatment of complicated inpatient SAM, the guidelines consist of three distinct&#xD;
      phases of treatment: phase 1 or stabilization phase where a low protein, liquid diet (F75) is&#xD;
      introduced with a reduced energy intake (80-100 kcal/kg/day). Once a child has stabilised,&#xD;
      there is a 'transition phase' consisting of either ready to use therapeutic foods (RUTF) with&#xD;
      supplemental F75 or alternatively another milk formula known as F100. RUTF is a peanut based,&#xD;
      energy dense supplement used to obtain catch-up growth. F100 is a liquid formula with a&#xD;
      higher energy density and protein content than F75. The caloric intake is increased daily to&#xD;
      a maximum of 130 kcal/kg/day. Finally, 'Phase 3' is the recovery phase during which the aim&#xD;
      is to achieve catch-up growth with either RUTF or F100.&#xD;
&#xD;
      Typically, the highest mortality rate is found in the early phases of treatment. Children who&#xD;
      fail treatment early often have profuse diarrhoea, signs of circulatory insufficiency which&#xD;
      is hard to treat. The most recent reports from Zambia and Kenya note a prevalence of&#xD;
      diarrhoea of more than 60% amongst children with SAM and it is associated with increased&#xD;
      mortality. Currently at Kilifi County Hospital and Coast Provincial General Hospital, ~20% of&#xD;
      children are given either a diluted or lactose-free milk feed during rehabilitation of SAM,&#xD;
      although there are no specific guidelines for this. Diarrhoea may be caused by a viral or&#xD;
      bacterial gastroenteritis, sepsis, or may be nutritionally induced (osmotic). There are no&#xD;
      routinely available tests to distinguish osmotic from infective or other causes of diarrhoea&#xD;
      in hospitals in sub-Saharan Africa.&#xD;
&#xD;
      The proportion of energy derived from carbohydrates in F75 is high. The carbohydrates in F75&#xD;
      milk (as well as F100 and RUTF) consist of a mixture of maltodextrin, sucrose and lactose.&#xD;
      Disaccharides such as maltose, lactose or sucrose are normally hydrolysed into&#xD;
      monosaccharides by disaccharidases localized at the tip of small intestinal villi. The&#xD;
      monosaccharides such as glucose and galactose can then be transported across the apical&#xD;
      membrane through Na+ dependent glucose transporter, whilst fructose makes use of a&#xD;
      facilitative fructose transporter. There is limited information on the intestinal function&#xD;
      and intestinal carbohydrate absorption in malnourished children. However, data from Jamaica&#xD;
      and South Africa suggest that there is impaired absorption of disaccharides (lactose and&#xD;
      sucrose), regardless of the presence or suspicion of gastroenteritis. Limited histological&#xD;
      evidence has shown intestinal atrophy in children with SAM. These data are consistent with&#xD;
      clinical signs of lactose malabsorption found in children with severe malnutrition. Recently,&#xD;
      evidence of impaired absorption of monosaccharide glucose in children with SAM was reported&#xD;
      in Malawi.&#xD;
&#xD;
      Apart from diarrhoea, early deterioration may also be related to severe metabolic&#xD;
      derangements due to a sudden change from a catabolic to an anabolic state, resulting in&#xD;
      refeeding syndrome. Refeeding syndrome is characterized by hypophosphataemia, hypokalaemia,&#xD;
      hypomagnesaemia and sodium retention. These severe electrolyte disturbances can lead to&#xD;
      impaired cardiac, pulmonary and neurological function and are often hard to treat. By&#xD;
      receiving energy predominantly from sugars, pancreatic insulin secretion is increased which&#xD;
      induces uptake of electrolytes including phosphate and potassium, into cells. Furthermore, as&#xD;
      protein synthesis is stimulated, increased production of adenosine tri-phosphate (ATP) leads&#xD;
      to a higher cellular demand for phosphate. Although insulin secretion appears to be partially&#xD;
      impaired in the early stages of refeeding, hypophosphatemia is a common feature during&#xD;
      refeeding of malnourished children, and is associated with mortality.&#xD;
&#xD;
      In this trial, the investigators aim to evaluate the outcome of using a revised formulation&#xD;
      of F75 milk with reduced carbohydrate composition and without lactose, compared to the&#xD;
      current formulation of F75 during the initial stabilisation period amongst children with&#xD;
      severe acute malnutrition. In the new formulation, more will be provided by lipids and the&#xD;
      total energy provided will be unchanged. The trial will be undertaken in two hospitals in&#xD;
      Kenya and one hospital in Malawi.&#xD;
&#xD;
      Enrolment and follow up was completed in December 2015, laboratory analysis of plasma and&#xD;
      faecal samples in ongoing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2014</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">December 2015</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to Stabilization</measure>
    <time_frame>During inpatient admission</time_frame>
    <description>The criteria for stabilisation will be according to WHO guidelines:&#xD;
- Absence of any WHO danger or emergency signs: obstructed breathing, respiratory distress, cyanosis, shock (delayed capillary refill plus fast &amp; weak pulse plus temperature gradient), severe anaemia (Hb&lt;5g/dl), congestive cardiac failure, impaired consciousness, convulsions, severe dehydration, profuse watery diarrhoea, vomits everything, hypothermia.&#xD;
and&#xD;
If there is oedema at baseline, loss of oedema defined as improving from a severe +++ oedema (severe: generalized bilateral pitting oedema including feet, legs, arms and face) to ++ oedema (moderate: no upper arm or upper leg oedema and no facial oedema or from ++ oedema to + (mild: only feet/ankle oedema) or none; and&#xD;
Tolerating full prescribed volume of F75 feeds and observed to be completing the feeds.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number days with diarrhoea</measure>
    <time_frame>Upto discharge from hospital participants will be followed for the duration of hospital stay, an expected average of 2 weeks</time_frame>
    <description>3 or more loose stools in the last 24 hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number days requiring rehydration fluids</measure>
    <time_frame>Upto discharge from hospital, an expected average of 2 weeks</time_frame>
    <description>Described as the number of days requiring Resomal or IV fluids</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage change in weight to day 5</measure>
    <time_frame>Up to day 5 of admission</time_frame>
    <description>Percentage change in weight between admission and day 5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in electrolyte serum electrolytes to day 3</measure>
    <time_frame>Between baseline (admission) and day 3</time_frame>
    <description>Changes in sodium, potassium, magnesium, calcium, phosphate and albumin between admission and day 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of new onset severe clinical deterioration</measure>
    <time_frame>Upto discharge from hospital, an expected average of 2 weeks</time_frame>
    <description>numbers of episodes of new onset severe clinical deterioration accompanied by one or more of the following features: shock (fast and weak pulse and limb versus core temperature gradient and capillary refill time&gt;3 seconds), respiratory distress (subcostal chest wall indrawing, hypoxaemia (SaO2) or requiring oxygen); impaired consciousness (Blantyre coma score&lt;4) or hypoglycaemia (&lt;3.0 mmol/l);</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Upto discharge from hospital, an expected average of 2 weeks</time_frame>
    <description>Mortality until discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to discharge from hospital</measure>
    <time_frame>Time to discharge from hospital, an expected average of 2 weeks</time_frame>
    <description>Time in days from admission to date of discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total days spent in stabilization phase</measure>
    <time_frame>During inpatient admission, an expected average of 2 weeks</time_frame>
    <description>Total days spent in stabilization phase, including periods when the child may go back to the stabilization phase during deterioration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of children with diarrhoeal pathogen detected</measure>
    <time_frame>During inpatient admission, an expected average of 2 weeks</time_frame>
    <description>The proportion of children with a diarrheal pathogen detected and plasma and fecal bio makers of gut inflammation and permeability</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">842</enrollment>
  <condition>Malnutrition</condition>
  <condition>Diarrhoea</condition>
  <condition>Metabolic Disturbance</condition>
  <arm_group>
    <arm_group_label>Standard F75 Milk</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>F75 with 63% of total energy from carbohydrates, including 10% of energy from lactose (standard F75).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Modified F75 Milk</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>F75 milk with 43% of total energy from carbohydrates, without any lactose, and providing the same amount of energy as standard F75 by increased lipid in the form of medium chain triglycerides.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Standard F75 Milk</intervention_name>
    <description>This is the standard F75 milk used worldwide (Control group)</description>
    <arm_group_label>Standard F75 Milk</arm_group_label>
    <other_name>Standard formulation F75 therapeutic milk</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Modified F75 Milk</intervention_name>
    <description>This is the experimental group</description>
    <arm_group_label>Modified F75 Milk</arm_group_label>
    <other_name>Modified formulation F75 Milk</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age 6 months to 13 years&#xD;
&#xD;
        Severe malnutrition defined as: mid upper arm circumference (MUAC) &lt;11.5cm if less than 5&#xD;
        years old;19 or weight for height Z score &lt;-3; or kwashiorkor as defined in the current&#xD;
        Kenyan and WHO guidelines.&#xD;
&#xD;
        Admitted to hospital because of medical complications or failure of an appetite test as&#xD;
        defined in the current WHO guidelines.&#xD;
&#xD;
        Eligible to start F75 milk by current WHO guidelines.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Declined to give informed consent.&#xD;
&#xD;
        Known allergy to milk products.&#xD;
&#xD;
        Any other reason the consenting investigator thinks that in the child's best interests it&#xD;
        inappropriate for them to take part.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>13 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James A Berkley</last_name>
    <role>Principal Investigator</role>
    <affiliation>KEMRI-Wellcome Trust Research Kilifi, Kenya</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Wieger Voskuijl</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Medicine, Blantye Malawi</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Robert Bandsma, PhD</last_name>
    <role>Study Director</role>
    <affiliation>The Hospital for Sick Children, Toronto, Canada</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kilifi County Hospital</name>
      <address>
        <city>Kilifi</city>
        <state>Coast</state>
        <zip>80108</zip>
        <country>Kenya</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Coast Provincial General Hospital - Study site</name>
      <address>
        <city>Mombasa</city>
        <country>Kenya</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital- Study site</name>
      <address>
        <city>Blantyre</city>
        <country>Malawi</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Kenya</country>
    <country>Malawi</country>
  </location_countries>
  <link>
    <url>http://www.medcol.mw/</url>
    <description>College of Medicine, Blantyre, Malawi.</description>
  </link>
  <link>
    <url>http://www.kemri-wellcome.org/</url>
    <description>KEMRI/Wellcome Trust Research Programme</description>
  </link>
  <link>
    <url>http://www.sickkids.ca/</url>
    <description>Sick Kids, Toronto</description>
  </link>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>September 10, 2014</study_first_submitted>
  <study_first_submitted_qc>September 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 22, 2014</study_first_posted>
  <last_update_submitted>April 13, 2016</last_update_submitted>
  <last_update_submitted_qc>April 13, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 14, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>severe acute malnutrition</keyword>
  <keyword>wasting</keyword>
  <keyword>kwashiorkor</keyword>
  <keyword>nutrition</keyword>
  <keyword>feeding</keyword>
  <keyword>milk</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malnutrition</mesh_term>
    <mesh_term>Severe Acute Malnutrition</mesh_term>
    <mesh_term>Diarrhea</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02246296
org study id: OXTREC 58-14
secondary id: P.03/14/1540
secondary id: SSC 2799
nct id: NCT02246296
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Time to Stabilization
time frame: During inpatient admission
description: The criteria for stabilisation will be according to WHO guidelines:
- Absence of any WHO danger or emergency signs: obstructed breathing, respiratory distress, cyanosis, shock (delayed capillary refill plus fast & weak pulse plus temperature gradient), severe anaemia (Hb<5g/dl), congestive cardiac failure, impaired consciousness, convulsions, severe dehydration, profuse watery diarrhoea, vomits everything, hypothermia.
and
If there is oedema at baseline, loss of oedema defined as improving from a severe +++ oedema (severe: generalized bilateral pitting oedema including feet, legs, arms and face) to ++ oedema (moderate: no upper arm or upper leg oedema and no facial oedema or from ++ oedema to + (mild: only feet/ankle oedema) or none; and
Tolerating full prescribed volume of F75 feeds and observed to be completing the feeds.
measure: Number days with diarrhoea
time frame: Upto discharge from hospital participants will be followed for the duration of hospital stay, an expected average of 2 weeks
description: 3 or more loose stools in the last 24 hours
measure: Number days requiring rehydration fluids
time frame: Upto discharge from hospital, an expected average of 2 weeks
description: Described as the number of days requiring Resomal or IV fluids
measure: Percentage change in weight to day 5
time frame: Up to day 5 of admission
description: Percentage change in weight between admission and day 5
measure: Change in electrolyte serum electrolytes to day 3
time frame: Between baseline (admission) and day 3
description: Changes in sodium, potassium, magnesium, calcium, phosphate and albumin between admission and day 3
measure: Number of new onset severe clinical deterioration
time frame: Upto discharge from hospital, an expected average of 2 weeks
description: numbers of episodes of new onset severe clinical deterioration accompanied by one or more of the following features: shock (fast and weak pulse and limb versus core temperature gradient and capillary refill time>3 seconds), respiratory distress (subcostal chest wall indrawing, hypoxaemia (SaO2) or requiring oxygen); impaired consciousness (Blantyre coma score<4) or hypoglycaemia (<3.0 mmol/l);
measure: Mortality
time frame: Upto discharge from hospital, an expected average of 2 weeks
description: Mortality until discharge
measure: Time to discharge from hospital
time frame: Time to discharge from hospital, an expected average of 2 weeks
description: Time in days from admission to date of discharge
measure: Total days spent in stabilization phase
time frame: During inpatient admission, an expected average of 2 weeks
description: Total days spent in stabilization phase, including periods when the child may go back to the stabilization phase during deterioration
measure: Proportion of children with diarrhoeal pathogen detected
time frame: During inpatient admission, an expected average of 2 weeks
description: The proportion of children with a diarrheal pathogen detected and plasma and fecal bio makers of gut inflammation and permeability
arm group label: Standard F75 Milk
arm group type: Active Comparator
description: F75 with 63% of total energy from carbohydrates, including 10% of energy from lactose (standard F75).
arm group label: Modified F75 Milk
arm group type: Experimental
description: F75 milk with 43% of total energy from carbohydrates, without any lactose, and providing the same amount of energy as standard F75 by increased lipid in the form of medium chain triglycerides.
intervention type: Dietary Supplement
intervention name: Standard F75 Milk
description: This is the standard F75 milk used worldwide (Control group)
arm group label: Standard F75 Milk
other name: Standard formulation F75 therapeutic milk
intervention type: Dietary Supplement
intervention name: Modified F75 Milk
description: This is the experimental group
arm group label: Modified F75 Milk
other name: Modified formulation F75 Milk
criteria: 
gender: All
minimum age: 6 Months
maximum age: 13 Years
healthy volunteers: No
last name: James A Berkley
role: Principal Investigator
affiliation: KEMRI-Wellcome Trust Research Kilifi, Kenya
last name: Wieger Voskuijl
role: Principal Investigator
affiliation: University of Medicine, Blantye Malawi
last name: Robert Bandsma, PhD
role: Study Director
affiliation: The Hospital for Sick Children, Toronto, Canada
facility: 
facility: 
facility: 
country: Kenya
country: Malawi
url: http://www.medcol.mw/
description: College of Medicine, Blantyre, Malawi.
url: http://www.kemri-wellcome.org/
description: KEMRI/Wellcome Trust Research Programme
url: http://www.sickkids.ca/
description: Sick Kids, Toronto
responsible party type: Sponsor
mesh term: Malnutrition
mesh term: Severe Acute Malnutrition
mesh term: Diarrhea