Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Reformulated F75 Milk to Treat Severe Acute Malnutrition (F75)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02246296
Recruitment Status : Completed
First Posted : September 22, 2014
Last Update Posted : April 14, 2016
Sponsor:
Collaborators:
KEMRI-Wellcome Trust Collaborative Research Program
University of Malawi College of Medicine
The Hospital for Sick Children
University of Groningen
Information provided by (Responsible Party):
University of Oxford

Tracking Information
First Submitted Date  ICMJE September 10, 2014
First Posted Date  ICMJE September 22, 2014
Last Update Posted Date April 14, 2016
Study Start Date  ICMJE December 2014
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2014)
Time to Stabilization [ Time Frame: During inpatient admission ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2014)
  • 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 ]
    3 or more loose stools in the last 24 hours
  • Number days requiring rehydration fluids [ Time Frame: Upto discharge from hospital, an expected average of 2 weeks ]
    Described as the number of days requiring Resomal or IV fluids
  • Percentage change in weight to day 5 [ Time Frame: Up to day 5 of admission ]
    Percentage change in weight between admission and day 5
  • Change in electrolyte serum electrolytes to day 3 [ Time Frame: Between baseline (admission) and day 3 ]
    Changes in sodium, potassium, magnesium, calcium, phosphate and albumin between admission and day 3
  • Number of new onset severe clinical deterioration [ Time Frame: Upto discharge from hospital, an expected average of 2 weeks ]
    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);
  • Mortality [ Time Frame: Upto discharge from hospital, an expected average of 2 weeks ]
    Mortality until discharge
  • Time to discharge from hospital [ Time Frame: Time to discharge from hospital, an expected average of 2 weeks ]
    Time in days from admission to date of discharge
  • Total days spent in stabilization phase [ Time Frame: During inpatient admission, an expected average of 2 weeks ]
    Total days spent in stabilization phase, including periods when the child may go back to the stabilization phase during deterioration
  • Proportion of children with diarrhoeal pathogen detected [ Time Frame: During inpatient admission, an expected average of 2 weeks ]
    The proportion of children with a diarrheal pathogen detected and plasma and fecal bio makers of gut inflammation and permeability
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Reformulated F75 Milk to Treat Severe Acute Malnutrition
Official Title  ICMJE Randomized Controlled Trial of a Reduced Carbohydrate Formulation of F75 Therapeutic Milk Among Children With Severe Acute Malnutrition
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Malnutrition
  • Diarrhoea
  • Metabolic Disturbance
Intervention  ICMJE
  • Dietary Supplement: Standard F75 Milk
    This is the standard F75 milk used worldwide (Control group)
    Other Name: Standard formulation F75 therapeutic milk
  • Dietary Supplement: Modified F75 Milk
    This is the experimental group
    Other Name: Modified formulation F75 Milk
Study Arms  ICMJE
  • Active Comparator: Standard F75 Milk
    F75 with 63% of total energy from carbohydrates, including 10% of energy from lactose (standard F75).
    Intervention: Dietary Supplement: Standard F75 Milk
  • Experimental: Modified F75 Milk
    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: Dietary Supplement: Modified F75 Milk
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 13, 2016)
842
Original Estimated Enrollment  ICMJE
 (submitted: September 19, 2014)
840
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Age 6 months to 13 years

Severe malnutrition defined as: mid upper arm circumference (MUAC) <11.5cm if less than 5 years old;19 or weight for height Z score <-3; or kwashiorkor as defined in the current Kenyan and WHO guidelines.

Admitted to hospital because of medical complications or failure of an appetite test as defined in the current WHO guidelines.

Eligible to start F75 milk by current WHO guidelines.

Exclusion Criteria:

Declined to give informed consent.

Known allergy to milk products.

Any other reason the consenting investigator thinks that in the child's best interests it inappropriate for them to take part.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 13 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Kenya,   Malawi
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02246296
Other Study ID Numbers  ICMJE OXTREC 58-14
P.03/14/1540 ( Other Identifier: COMREC Blantyre Malawi )
SSC 2799 ( Other Identifier: KEMRI ERC Kenya )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Oxford
Study Sponsor  ICMJE University of Oxford
Collaborators  ICMJE
  • KEMRI-Wellcome Trust Collaborative Research Program
  • University of Malawi College of Medicine
  • The Hospital for Sick Children
  • University of Groningen
Investigators  ICMJE
Principal Investigator: James A Berkley KEMRI-Wellcome Trust Research Kilifi, Kenya
Principal Investigator: Wieger Voskuijl University of Medicine, Blantye Malawi
Study Director: Robert Bandsma, PhD The Hospital for Sick Children, Toronto, Canada
PRS Account University of Oxford
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP