Evaluating the effectiveness of a legume-enriched nutritional intervention, in treatment of severe undernutrition in children

ISRCTN	ISRCTN10309022
DOI	https://doi.org/10.1186/ISRCTN10309022
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	17IC4146
Sponsor	Imperial College London
Funders	Medical Research Council, Wellcome Trust Institutional Strategic Support Fund, National Institute for Health Research (NIHR) - Research Imperial Biomedical Research Centre (BRC), Engineering and Physical Sciences Research Council (ESPRC) Impact Acceleration Account, Royal Marsden NHS Foundation Trust, UK Research and Innovation - Global Challenges Research Fund

Submission date: 18/05/2018
Registration date: 23/05/2018
Last edited: 04/06/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Severe acute malnutrition is a serious illness and a common problem. In malnutrition, the gut becomes damaged and does not function properly. This means a lot of the food is lost in the stool, sometimes as diarrhoea, and not enough food gets into the body. Healthy bacteria live in the gut and do not cause any illness, but the types of bacteria may change in malnutrition to ones that can cause serious infections. Good bacteria use food that the body cannot digest (fibre/roughage) and turn it into helpful products. The Uganda Ministry of Health, UNICEF and the WHO recommend special feeds (F75/F100) to treat children with malnutrition in order to increase the amount of energy and nutrients received. These feeds do not contain any fibre/roughage, so numbers of good bacteria may decrease. They also contain a common milk sugar called lactose, which normally does not cause any problems. However, due to damage to the gut, this may be poorly digested, making diarrhoea worse and making it more difficult for the child to recover. If bad bacteria are present, they could use this sugar, increasing the risk of infection. The aim of this study is to see whether giving children an altered nutritional feed helps repair the gut and encourage the good bacteria, which may reduce illness or improve recovery. In the study the standard nutritional feed that all children with severe malnutrition receive routinely is altered by removing the lactose and adding a chickpea flour. Chickpea flour contains fibre/roughage that can help good bacteria. The aim is to find the best nutritional treatment for children with severe malnutrition.

Who can participate?
Children aged 6 months to 5 years with severe acute malnutrition

What does the study involve?
Participants are randomly allocated to receive standard treatment (F75/F100) or the lactose-free, chickpea flour feed which provides similar amounts of energy and nutrients. Treatment is for 14 days, followed by standard treatment as required. This includes provision of ready to use therapeutic feeds until the child has recovered. Children are followed up for 90 days.

What are the possible benefits and risks of participating?
Benefits include closer observation during admission which consequently may allow the clinical team to make important changes to the child’s treatment during in hospital stay. All routine non-study medications required by the hospital to treat the child will be made available. The parents or guardians for the children will be asked to return for follow up at 28 days after admission. This additional visit will include a clinical review thus an opportunity for medical treatment if required. Education regarding nutrition will also be readdressed at this time. Reimbursement will be made for transport cost for this follow-up visit plus any treatment costs required during the visits. There are very few risks involved in this study. The chickpea flour feeds are used within the local diets but have been milled/processed in such a way to maximise their ability to ferment within the bowel to create a favourable microbiome. Intolerance or allergy is rare. The G6PD variant in these populations retains >12% of its activity thus not rendering G6PD deficient patients to susceptibility to oxidant stress (as seen in Mediterranean variants rendering them susceptible to ‘Favism’). Blood samples are required as part of this study; this includes routine bloods according national guidelines and an additional 12 ml over the whole duration of the study. Required volumes of blood will be minimized wherever possible and be within the locally agreed maximum. Urine and stool will be collected in a non-invasive manner thus should not cause any distress to the child or their family.

Where is the study run from?
Mbale Clinical Research Institute (Uganda)

When is the study starting and how long will it run for?
June 2018 to December 2019

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Mr Kevin Walsh

Contact information

Mr Kevin Walsh
Public

Division of Infectious Diseases
Department of Paediatrics
Faculty of Medicine
Imperial College London
3rd Floor SAF Building
South Kensington Campus
London
SW7 2AZ
United Kingdom

Study information

Primary study design	Interventional
Study design	Two-centre open-label randomised controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Modifying Intestinal integrity and the MicroBiome in severely malnourished children with LEgume-based Feeds to improve outcome compared to standard treatment: a randomised controlled trial
Study acronym	MIMBLE II
Study objectives	That legume-enriched, lactose-free nutrition support will improve outcomes in children with severe acute malnutrition, compared with standard nutritional rehabilitation milks as recommended by the World Health Organization
Ethics approval(s)	1. Imperial College Research Ethics Committee, 23/04/2018, ref: 17IC41456 2. Mbale Regional Referral Hospital REC, 09/05/2018, ref: MRRH-REC In – COM 019/2018 3. Uganda National Council for Science and Technology: applied March 2018
Health condition(s) or problem(s) studied	Severe acute malnutrition
Intervention	Randomisation will be in permuted blocks. Cards with treatment allocation (standard or altered standard with chickpea flour) will be prepared in Kilifi and sent to Mbale. They will be kept in numbered, sealed opaque envelopes, each signed across the seal. The cards will be numbered consecutively and will be opened in numerical order. Children will be randomised to a legume-enriched feed or standard treatment (WHO F75/F100) on a 1:1 basis: Control arm: World Health Organisation recommended F75 (0.75kcal/ml) and F100 (1kcal/ml) feeds Investigation arm: Lactose-free, chickpea enriched feed containing 2kcal/ml, provided in quantities to match energy provision in standard treatment. Treatment with randomised intervention/control will be for 14 days duration, followed by standard treatment as required. This includes provision of ready to use therapeutic feeds until child has recovered, defined by weight-for-height z-score >-2. The duration of this is variable. Children will be followed up to 90 days post admission date.
Intervention type	Supplement
Primary outcome measure(s)	1. Mid-upper arm circumference in centimeters and millimeters measured using measuring tape supplied by UNICEF designed for this purpose on admission (at trial recruitment), day 7, day 28 and day 90 2. Survival recorded by incidence of death up to day 90
Key secondary outcome measure(s)	Current secondary outcome measures as of 16/09/2021: 1. Weight measured daily from admission to discharge, then at day 28 and day 90, by clinical weighing scales. Daily weight (in grams and kilograms) change is calculated from this to assess response to the intervention, and moderate weight gain defined as being >5g/kg/day 2. Development of diarrhoea assessed by daily recording of stool passed during inpatient stay, and diagnosed if >3 watery stools are passed in any one day. Inpatient stay is variable, but likely to be minimum of 14 days. Children/parents are asked about number and consistency of stool passed at day 28 and day 90 reviews 3. Time to resolution of diarrhoea assessed in patients who presented with diarrhoea on admission (>3 watery stools in one day) during inpatient stay. Daily inpatient monitoring of stool passed is undertaken, and resolution defined as cessation of passing >3 watery stools in one day. Children/parents are asked about number and consistency of stool passed at day 28 and day 90 reviews 4. Presence of oedema recorded on admission assessed visually and severity recorded as affecting pretibial only (mild), involving hands/feet (moderate), or generalised (severe). Oedema monitored daily during inpatient admission, and at time to resolution noted. Presence of oedema assessed at day 28 and day 90 reviews also 5. Faecal calprotectin (by ELISA) used to assess inflammation in the gut, analysed on collected faecal samples at admission, day 7, day 28 and day 90 6. Safety assessed by reports of serious adverse events to include any untoward medical occurrence or effect that is 1) fatal, 2) life threatening, 3) permanently or temporarily disabling or incapacitating, 4) causes prolongation of hospital stay, or 5) any other event deemed to have a real risk of resulting in one of the previous outcomes. Allergic reactions will be considered SAEs. SAEs reported immediately to the on-site PI, and captured in a dedicated form at the time of event or the next clinical review. Previous secondary outcome measures: 1. Weight measured daily from admission to discharge, then at day 28 and day 90, by clinical weighing scales. Daily weight (in grams and kilograms) change is calculated from this to assess response to the intervention, and moderate weight gain defined as being >5g/kg/day 2. Development of diarrhoea assessed by daily recording of stool passed during inpatient stay, and diagnosed if >3 watery stools are passed in any one day. Inpatient stay is variable, but likely to be minimum of 14 days. Children/parents are asked about number and consistency of stool passed at day 28 and day 90 reviews 3. Time to resolution of diarrhoea assessed in patients who presented with diarrhoea on admission (>3 watery stools in one day) during inpatient stay. Daily inpatient monitoring of stool passed is undertaken, and resolution defined as cessation of passing >3 watery stools in one day. Children/parents are asked about number and consistency of stool passed at day 28 and day 90 reviews 4. Presence of oedema recorded on admission assessed visually and severity recorded as affecting pretibial only (mild), involving hands/feet (moderate), or generalised (severe). Oedema monitored daily during inpatient admission, and at time to resolution noted. Presence of oedema assessed at day 28 and day 90 reviews also 5. Faecal calprotectin (by ELISA) used to assess inflammation in the gut, analysed on collected faecal samples at admission, day 7, day 28 and day 90
Completion date	01/09/2019

Eligibility

Participant type(s)	Patient
Age group	Child
Sex	All
Target sample size at registration	160
Total final enrolment	160
Key inclusion criteria	1. Marasmus defined by mid-upper arm circumference < 11.5cm 2. Kwashiorkor defined as symmetrical pitting oedema involving at least the feet irrespective of WHZ score or MUAC 3. Guardian/parent willing and able to provide consent
Key exclusion criteria	Children with severe acute malnutrition with very high risk of death due to comorbidity, e.g. malignant disease or terminal illness
Date of first enrolment	05/07/2018
Date of final enrolment	28/08/2019

Locations

Countries of recruitment

Uganda

Study participating centres

Mbale Clinical Research Institute

Mbale Regional Referral Hospital, Plot 29-33 Pallisa Road
Mbale
-
Uganda

Soroti Regional Referral Hospital

Hospital Road
PO Box 289
Soroti
-
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Gary Frost (gary.frost@imperial.ac.uk). Anonymised data including clinical and anthropometric data will be made available, including results of any experimental analysis completed including faecal calprotectin, metataxonomic data, and metabolomic data. Data will be made available by reasonable request following the publication of the trial results (anticipated 01/09/2020), and following subsequent publication metataxonomic data, and metabolomic data so long as this does not conflict with planned ongoing analysis or sub-analyses and for 10 years following this date. The data used in this research was collected subject to the informed consent of the participants. Access to the data will only be granted in line with that consent, subject to approval by the project ethics board and under a formal Data Sharing Agreement.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		27/01/2023	07/03/2023	Yes	No
Results article		04/06/2024	04/06/2024	Yes	No
Protocol article	protocol	02/08/2018		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 3.1	06/10/2018	15/08/2023	No	No

Additional files

ISRCTN10309022 MIMBLE Protocol v3.1_06Oct2018.pdf: Protocol file

Editorial Notes

04/06/2024: Publication reference and total final enrolment added.
15/08/2023: The following changes were made to the trial record:
1. Uploaded protocol (not peer-reviewed) as an additional file.
2. The study design was changed from "Single-centre open-label randomised controlled trial" to "Two-centre open-label randomised controlled trial".
3. The study participating centre Soroti Regional Referral Hospital was added.
07/03/2023: Publication reference added.
16/09/2021: The following changes have been made:
1. The secondary outcome measures have been updated.
2. The recruitment start date has been changed from 11/06/2018 to 05/07/2018.
3. The recruitment end date has been changed from 01/12/2018 to 28/08/2019.
4. The intention to publish date has been changed from 01/03/2021 to 01/12/2021.
02/10/2020: The intention to publish date was changed from 01/09/2020 to 01/03/2021.
23/10/2018: Publication reference added.