A trial of different nutritional supplements and subsequent support to secure and sustain the recovery of moderately undernourished young children recovering from an illness
| ISRCTN | ISRCTN53213318 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN53213318 |
| Secondary identifying numbers | 0.151 |
- Submission date
- 26/12/2022
- Registration date
- 03/04/2023
- Last edited
- 06/11/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Nutritional, Metabolic, Endocrine
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English Summary
Background and study aims
Moderate wasting is associated with a threefold higher risk of death in children under 5 years of age compared with their well-nourished peers. These deaths largely occur from infectious illnesses. The interactions between episodic infections and malnutrition are complex and bi-directional. There are very no clinical trials that have been done in this high-risk subgroup to investigate if it is possible to break the malnutrition-infection cycle and decrease the risk of deterioration/death by initiating interventions targeting the nutritional (anthropometric) deficit. The NUTRIMAM trial proposes to evaluate different nutritional supplements in young children who are moderately wasted and present with an acute infection.
The NUTRI-MAM trial will aim to evaluate the effectiveness of locally available foods (LAF) or microbiota-directed supplementary food (MDSF) compared to ready-to-use supplementary food (RUSF), when given to moderately wasted children presenting to health facilities with an acute illness, on initial anthropometric recovery (within 12 weeks of enrolment) and sustained recovery (at 24 weeks after enrolment).
Who can participate?
Moderately wasted children 6-24 months of age with an acute illness (diarrhoea, pneumonia, fever or malaria) in Bangladesh, India and Pakistan, Mali and Tanzania
What does the study involve?
Phase 1 of the study involves daily intake of the study supplement (RUSF, MDSF or LAF) for 12 weeks. Children who recover anthropometrically from moderate wasting will be randomised into a second phase to a follow-up intervention (including counseling and food vouchers) vs standard of care to assess the effect of continued follow-up on sustaining this recovery.
What are the possible benefits and risks of participating?
The child may benefit from the nutritional supplement received as part of the study, as these will provide additional nutrients that will help them to grow. The caregiver will be able to discuss the child’s growth and feeding habits with a trained counselor from the clinic.
It is possible that the child/family may not receive any direct benefit from taking part in the study. The study foods are commonly used and known to be safe for children. A few children may react to the foods. Reactions may include rash, itching, diarrhoea, nausea, vomiting and abdominal pain.
Where is the study run from?
World Health Organisation (Switzerland)
When is the study starting and how long is it expected to run for?
January 2021 to December 2025
Who is funding the study?
Bill and Melinda Gates Foundation (USA)
Who is the main contact?
Dr Ayesha De Costa, deay@who.int
Contact information
Dr Ayesha De Costa
Scientific
Scientific
Dept of Maternal, newborn, Child and Adolescent Health
World Health Organization
Geneva
1211
Switzerland
| Phone | +41 (0)227 911 965 |
|---|---|
| deay@who.int |
Study information
| Study design | Multi-center open-label sequential multiple assignment randomized trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A multi-country, multi-centre, three-arm, parallel-group, open-label, randomized trial of three supplements for the nutritional management of moderate wasting in children 6-24 months of age with acute illness |
| Study acronym | NUTRIMAM |
| Study hypothesis | This trial has three hypotheses: 1. That supplementation with (i) locally available food (LAF) will be non-inferior to supplementation with ready-to-use supplementary food (RUSF) on the proportion of moderately wasted children showing initial anthropometric recovery by week 12 post-enrolment (ii) and superior to RUSF on the proportion showing sustained recovery by week 24 post-enrolment. 2. That supplementation with microbiome-directed supplementary food (MDSF) will be superior to supplementation with RUSF on the proportion of moderately wasted children showing initial anthropometric recovery by week 12 post-enrolment and sustained recovery by week 24 post-enrolment 3. That active follow-up of the recovered child including counselling and food vouchers will result in higher rates of sustained recovery at 24 weeks |
| Ethics approval(s) | Approved 12/10/2022, WHO research ethics committee (Av Appia 20, Geneve 1211, Switzerland; Tel: not applicable; ercsec@who.int), ref: ERC.0003631 |
| Condition | Moderate wasting in children 6-24 months of age |
| Intervention | Phase 1: Children are randomised to one of three treatment arms: ready-to-use supplementary food (RUSF), locally available food (LAF) or microbiome-directed supplementary food (MDSF). This supplement will be provided daily for 12 weeks. Each day’s provision would comprise 50% of the estimated daily caloric requirement. Phase 2: Children who recover anthropometrically in phase 1 will be randomised at the end of the 12 weeks of phase 1 into one of two groups for phase 2: follow-up intervention (comprising counselling on appropriate feeding practices and recognising need referral, monthly food vouchers) for a further 12 weeks OR standard of care i.e. follow up at the end of 12 weeks. Randomisation for both phases: online electronic randomisation system. A nested observational sub-study of the main NUTRIMAM trial will be conducted in NUTRIMAM sites located in Bangladesh, India, Mali, Pakistan and Tanzania. A representative sample of children aged 6-17 months (stratified 6-11 months and 12-17 months for some outcomes) who are enrolled in the main NUTRIMAM trial will be involved. The sub-study includes three components: 1. Microbiome/multi-omics measures, 2. Measures of EED and systemic and local inflammation, and, 3. Body composition Body composition assessments via deuterium dilution will be conducted at all five NUTRIMAM sites. Due to funding constraints, the EED and microbiome/multi-omics components will only be performed at three sites (Bangladesh, Mali and Tanzania). If additional funding becomes available, the full range of assessments will also be conducted in India and Pakistan. Additionally, in sites conducting the microbiome/multi-omics measures, a healthy reference cohort (HRC) of infants 5-6 months of age will be established from the same catchment population from which the NUTRIMAM trial population is enrolled and followed until 24 months of age. The purpose of the HRC is to allow characterisation of the gut flora of healthy children in the absence of infection and inflammation and thereby enable comparison of baseline and follow-up gut flora examination of wasted children including responses to nutrition interventions. Previous interventions: Phase 1: Children are randomised to one of three treatment arms: ready-to-use supplementary food (RUSF), locally available food (LAF) or microbiome-directed supplementary food (MDSF). This supplement will be provided daily for 12 weeks. Each day’s provision would comprise 50% of the estimated daily caloric requirement. Phase 2: Children who recover anthropometrically in phase 1 will be randomised at the end of the 12 weeks of phase 1 into one of two groups for phase 2: follow-up intervention (comprising counselling on appropriate feeding practices and recognising need referral, monthly food vouchers) for a further 12 weeks OR standard of care i.e. follow up at the end of 12 weeks. Randomisation for both phases: online electronic randomisation system. |
| Intervention type | Mixed |
| Primary outcome measure | Phase 1: Anthropometric recovery at week 12 (defined as recovery from moderate wasting on weight-for-length z score [WLZ] or mid upper arm circumference [MUAC]) Phase 2: Anthropometric recovery at week 24 (defined as recovery from moderate wasting on weight-for-length z score or mid upper arm circumference) Recovery is defined as WLZ >-2.0 or MUAC ≥125 mm (depending on whether the child was ascertained to have moderate wasting at enrolment based on a WLZ <-2 or a MUAC <125 mm or both. The child must show improvement on the parameter (WLZ >-2.0 or MUAC ≥125 mm) that indicated moderate wasting at enrolment. If the child was moderately wasted on both parameters, improvement on any one as defined above is accepted as recovery. |
| Secondary outcome measures | Current secondary outcome measures as of 28/03/2024: 1. Time to recovery between the three groups within the first 12 weeks 2. Mean change in i) Mid-upper arm circumference (MUAC, in mm), ii) Weight-for-length z-score (WLZ), iii) Weight-for-age z-score (WAZ), iv) Length-for-age z-score (LAZ): - between MDSF, LAF and RUSF from i) enrolment to 12 weeks and ii) enrolment to 24 weeks - between food voucher and standard care post-recovery support groups from week 12 to week 24 3. Mean change in skinfold thickness measurements: - between MDSF, LAF and RUSF from i) enrolment to 12 weeks and ii) enrolment to 24 weeks - between food voucher and standard care post-recovery support groups from week 12 to week 24 4. Deterioration to SAM or death: - between MDSF, LAF and RUSF from i) enrolment to 12 weeks and ii) enrolment to 24 weeks - between food voucher and standard care post-recovery support groups from week 12 to week 24 5. All-cause mortality: - between MDSF, LAF and RUSF from i) enrolment to 12 weeks and ii) enrolment to 24 weeks - between food voucher and standard care post-recovery support groups from week 12 to week 24 6. Any hospitalisation (>24h): - between MDSF, LAF and RUSF from i) enrolment to 12 weeks and ii) enrolment to 24 weeks - between food voucher and standard care post-recovery support groups from week 12 to week 24 7. Deterioration to SAM: - between MDSF, LAF and RUSF from i) enrolment to 12 weeks and ii) enrolment to 24 weeks - between food voucher and standard care post-recovery support groups from week 12 to week 24 Additional exploratory outcomes We will also do an exploratory analyses of MDSF as compared to. LAF for all primary and secondary outcomes. _____ Previous secondary outcome measures: 1. Time to anthropometric recovery within the first 12 weeks (time-to-event): this will be defined as the number of days to anthropometric recovery within the first 12 weeks. The day of anthropometric recovery will be the visit day of recovery 2. Anthropometric recovery from moderate wasting at any point up to 12 weeks after enrolment, compared between MDSF vs LAF groups 3. Mean change in MUAC measured using MUAC tapes from enrollment to 12 weeks: This will be the 12-week MUAC value minus the baseline MUAC value 4. Mean change in WLZ (weight measured with baby weighing scale, length measured with length board) from enrollment to 12 weeks: This will be the 12-week WLZ value minus the baseline WLZ value 5. Mean change in weight for age Z score (WAZ) measured with baby weighing scale from enrollment to 12 weeks: This will be the 12-week WAZ value minus the baseline WAZ value 6. Mean change in length for age Z score (LAZ) measured using with length board from enrollment to 12 weeks: This will be the 12-week LAZ value minus the baseline LAZ value 7. Mean change in skinfold thickness measured using Holtain caliper from enrollment to 12 weeks: this will be the 12-week skinfold thickness measurements minus the baseline measurement value 8. Severe acute malnutrition (SAM) or mortality up to 12 weeks: this is a composite outcome of SAM or death up to 12 weeks. SAM will be defined as a WLZ < -3 z-score or MUAC <115 mm or the presence of bilateral pitting oedema at any follow-up visit during the first 12 weeks of the study. Mortality up to 12 weeks will include all deaths that occur on or before day 84 of follow-up (12 weeks) 9. 24-week sustained recovery: 24-week sustained recovery will be considered a secondary outcome for LAF vs MDSF. The definition will be the same as listed under the primary outcome measure above 10. Mortality to 12 weeks: mortality up to 12 weeks will include all deaths that occur on or before day 84 of follow-up (24 weeks). This is during the active intervention period 11. Hospitalization to 12 weeks: hospitalization will be defined as a stay in a health facility >24 hours. Only hospitalizations on or before day 84 of follow-up (12 weeks) will be considered as meeting the outcome. This is during the active intervention period. |
| Overall study start date | 01/01/2021 |
| Overall study end date | 31/12/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 6 Months |
| Upper age limit | 24 Months |
| Sex | Both |
| Target number of participants | 6360 |
| Participant inclusion criteria | 1. Age 6-24 months 2. Moderately wasted i.e. WLZ ≤-2 and > -3 or MUAC <125 mm and >115 mm 3. Presenting with any of the following acute illnesses at a facility out-patient clinic or discharged from hospital after <7 days for any of the following: 3.1. Diarrhea, defined as three or more loose or watery stools (with or without blood) in the previous 24 hours, and no dehydration on assessment. If the child has dehydration, the dehydration will be treated re-assessing for recruitment, or 3.2. Pneumonia, defined as the presence before of fast breathing or chest indrawing, or 3.3. Non-malarial fever, defined as reported or measured (≥38ᴼC) fever of >3 days but <7 days duration [Acute illness in the context of this trial: Children with significant acute illness are at higher risk for severe outcomes like risk of developing SAM or hospitalization/death. Decreasing the risk in these children is important. Therefore, acute illness in this trial will be defined as diarrhea, signs of pneumonia, malaria or fever. If fever, then this should be present for >3 days duration. Milder illnesses, for example, skin or common cold/ cough will not be considered as significant acute illness as having these mild illnesses are less likely to cause children to enter a downward spiral of increased risk of morbidity/mortality] 3.4. malaria, defined as reported or measured (≥38ᴼC) fever and positive rapid diagnostic test, or 4. Consent for study participation from parent or legal guardian |
| Participant exclusion criteria | Current exclusion criteria as of 28/03/2024: 1. Severe acute malnutrition (WLZ <-3 or MUAC <115 mm or oedema of both feet) 2. General danger signs (lethargic/unconscious, convulsions, unable to drink, vomits everything) 3. Severe illness (severe pneumonia or very severe disease, severe dehydration, neck stiffness) 4. Persistent diarrhoea (≥14 days) 5. Chronic infections/illness or disability, e.g. TB, HIV, congenital defects, cerebral palsy 6. Require hospital admission 7. Well child attended clinic only for routine growth monitoring or immunization 8. Child receiving food supplements for moderate wasting 9. Treated for moderate wasting in the previous 3 months 10. Previously enrolled in the study 11. Child with any known history of food allergy or food intolerance 12. Another child in the same household already recruited into the study 13. Child lives outside the study area routinely or will be outside of the study area for more than two weeks in the upcoming 3 months. _____ Previous exclusion criteria: 1. Severe acute malnutrition (WLZ <-3 or MUAC <115 mm or oedema of both feet) 2. General danger signs (lethargic/unconscious, convulsions, unable to drink, vomits everything) 3. Severe illness (severe pneumonia or very severe disease, severe dehydration, neck stiffness) 4. Persistent diarrhoea (≥14 days) 5. Chronic infections/illness or disability, e.g. TB, HIV, congenital defects, cerebral palsy 6. Require hospital admission 7. Well child attended clinic only for routine growth monitoring or immunization 8. Child receiving food supplements for moderate wasting 9. Treated for moderate wasting in the previous 3 months 10. Previously enrolled in the study 11. Child with any known history of food allergy or food intolerance 12. Another child in the same household already recruited into the study 13. Child lives outside the study area |
| Recruitment start date | 24/04/2023 |
| Recruitment end date | 30/06/2025 |
Locations
Countries of recruitment
- Bangladesh
- India
- Mali
- Nigeria
- Pakistan
- Tanzania
Study participating centres
International Centre for Diarrhoeal Disease Research
Mohakali
Dhaka
1212
Bangladesh
Dhaka
1212
Bangladesh
Center for Vaccine Development
Ex—Institut Marchoux
Avenue Mohamed VI
Djikoroni Para
Bamako
251
Mali
Avenue Mohamed VI
Djikoroni Para
Bamako
251
Mali
Center for Public Health Kinetics
214-A, Basement
Vinoba Puri
Lajpat Nagar II
New Delhi
-
India
Vinoba Puri
Lajpat Nagar II
New Delhi
-
India
The Aga Khan University Hospital
Stadium Road
Karachi
-
Pakistan
Karachi
-
Pakistan
Muhimbili University of Health and Allied Sciences
United Nations Rd
Dar es Salaam
-
Tanzania
Dar es Salaam
-
Tanzania
Sponsor information
World Health Organisation
Other
Other
Av. Appia 20
Geneva
1211
Switzerland
| Phone | +41 (0)227 911 965 |
|---|---|
| mncah@who.int | |
| Website | https://www.who.int/ |
Funders
Funder type
Charity
Bill and Melinda Gates Foundation
Government organisation / Trusts, charities, foundations (both public and private)
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Bill & Melinda Gates Foundation, Gates Foundation, BMGF, B&MGF, GF
- Location
- United States of America
Results and Publications
| Intention to publish date | 01/01/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Ayesha De Costa (deay@who.int). The type of data that will be shared: this will depend on the request Dates of availability: expected 2027 Whether consent from participants was required and obtained: only anonymised data will be shared |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 05/11/2024 | 06/11/2024 | Yes | No |
Editorial Notes
06/11/2024: Publication reference added.
14/05/2024: The interventions were changed to include a nested observational sub-study.
28/03/2024: The following changes were made to the trial record:
1. The secondary outcome measures were changed.
2. The exclusion criteria were changed.
18/04/2023: The recruitment start date was changed from 01/04/2023 to 24/04/2023.
05/01/2023: Trial's existence confirmed by the WHO research ethics committee.
