Clinical trial NCT06781918: Severe Acute Malnutrition and Child Development Clinical Trial in Mwanza
Official title: BRAIN DEVELOPMENT, GROWTH and HEALTH in CHILDREN with SEVERE ACUTE MALNUTRITION
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Severe Acute Malnutrition in Childhood
Keywords: Severe acute malnutrition
Ready to use therapeutic food
Childhood development
Psychosocial stimulation
Choline
Docosahexaenoic acid (DHA)
Lead sponsor: National Institute for Medical Research, Tanzania
Sponsor class: OTHER_GOV
Collaborators: name: University of Liverpool
name: Bugando Medical Centre
name: University of Turku
name: Rigshospitalet, Denmark
name: University of Copenhagen
name: Sokoine University of Agriculture
name: London School of Hygiene and Tropical Medicine
First posted: 2025-01-17
Enrollment: 800
Sex: ALL
Minimum age (years): 6
Maximum age (years): 36
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: This is a 2x2 factorial randomized clinical trial which aims to study the effects of DHA and choline enriched ready to use therapeutic foods and psychosocial stimulation in the management of children with severe acute malnutrition.
Primary purpose: TREATMENT

Brief summary: This is a randomized clinical trial to learn whether ready-to-use therapeutic foods enriched with choline and docosahexaenoic acid (DHA) together with psychosocial stimulating activities work well to improve child development in children with severe acute malnutrition(SAM). The overall question this trial aims to answer is can the health and development outcomes of children with SAM be improved through optimized nutritional treatment and integrated psychosocial support.

Researchers will compare the new ready-to-use therapeutic food and an integrated psychosocial stimulation to a standard look-alike nutritional supplement that contains no additional nutrients being investigated and the standard nutritional counseling given locally and assess its effects on child development in children with severe acute malnutrition.

Participants will:

* Be given the trial interventions which will be delivered over 12 weeks
* After the 12 weeks of intervention, participants will return for outcome evaluations (week 12 study visit), which will be repeated at follow-up visits after 24 and 48 weeks.

Detailed description: Background Estimated, 13.6 million children were affected by severe acute malnutrition (SAM) in 2022. Early childhood is a critical period of brain development and children exposed to malnutrition in early life have poorer school performance and lower income in adult life. Introduction of Ready to use therapeutic foods (RUTF) has greatly improved the nutritional recovery of children with SAM. However, SAM remains associated with adverse effects on child cognitive and social development. The balance in the RUTF between polyunsaturated n-6 and n-3 essential fatty acids (EFAs) in RUTF has been questioned. Essential fatty acid (EFA) status is associated with child development, and children given the standard RUTF do not improve their n-3 EFA status after recovery.

A trial in Malawi found a positive effect on cognitive scores six months after completing nutritional therapy with RUTF with added preformed docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid (PUFA) of the n-3 series, which is essential for neural growth. There is also a potential for improving the content of other nutrients of importance for neurodevelopment in early childhood like choline, which is essential for neurotransmitter synthesis and phospholipids in the brain. Studies have indicated a synergistic relationship between n-3 EFAs and choline, suggesting that low levels of one or both may negatively impact cognition.

Deficits in child development associated with SAM are not only caused by inadequate diets. Families exposed to malnutrition are often affected by psychological distress, consequently children are likely to be offered little stimulation and responsive care. However, in practice, support for psychosocial stimulation and responsive caregiving is rarely offered during hospital-based treatment, and it is still not included in the guidelines for community-based treatment of SAM. The intensity of this intervention is difficult under the constraints of most health services in low- and middle-income countries (LMIC). More recent packages for promoting responsive care have shown some effects, but often not when implemented at scale or within systems of care.

In this study we hypothesize that optimized nutritional treatment and integrated psychosocial support can improve the health and development outcomes of children with SAM.

Specific objectives:

1. to assess the effects of a modified RUTF and psychosocial stimulation, individually and combined, on attention, cognitive, motor, language and psycho-emotional development in children treated for SAM;
2. to investigate the pathways of intervention effects on cognitive development by assessing the role of DHA and choline status in the child as well as caregiver factors which include caregiver-child interaction, home stimulation and maternal psychological distress;
3. to assess how, why and for whom the modified RUTF and psychosocial interventions work within the trial context, perceptions of their feasibility of implementation within the routine health system, and the climate and environmental sustainability of interventions.

Methods:

This trial is designed as a 2x2 factorial randomized clinical trial to assess the effects of DHA and choline enriched vs. standard RUTF and psychosocial stimulation vs. standard counselling in management of SAM. Participants will be individually randomised to nutritional intervention arms and clusters will be randomized to psychosocial intervention arms.

The interventions will be delivered over a period of 12 weeks. After enrolment and baseline data collection, participants will receive their first RUTF sachets. They will then be requested to return to the study site for a total of seven visits during the intervention period to receive interventions. After the 12 weeks of intervention, participants will return for outcome evaluations (week 12 study visit), which will be repeated at follow-up visits after 24 and 48 weeks. The study will take place in Mwanza region, Tanzania. The trial will include children with uncomplicated SAM aged 6-36 months from eight health care facilities in Ilemela municipality, Nyamagana municipality and Magu district.

Outcomes:

The primary outcomes is the change in child development scores, which will be assessed at baseline, 12, 24 and 48 weeks and compared with intervention groups. These will assess gross, fine motor, language and psycho -emotional skills by validated tool called (MDAT) Malawi Development Assessment Tool) and neurocognitive function will be accessed by eye-tracking. Secondary outcomes will allow us to assess proximate effects of the interventions, which may mediate long-term effects on development

Analysis:

The primary analysis will be based on the intention-to-treat principle using available case data. The analysis will assess intervention effects based on the 2x2 factorial design by comparing changes in outcomes between baseline and intervention endline (i.e., 12 weeks) using a linear regression model adjusted for sex, age and month of inclusion to account for possible seasonal effects.

Secondary analysis will include assessment of intervention effects at 24- and 48-weeks follow-up using a linear mixed model to include repeated measurements. The models will include the baseline value of the outcome as fixed effect and participant as random effect to account for the correlation between measurements from the same participant. These models will also include adjustment for other variables as appropriate.

Secondary analyses will include per-protocol analyses to assess effects within groups with high compliance with the interventions

Ethics:

Ethical approval has been sought from the Medical Research Coordinating Committee (MRCC) of the National Institute for Medical Research in Tanzania and the London School of Hygiene and Tropical Medicine ethics committee.

Eligibility criteria: Inclusion Criteria:

1. Age from 6-36 months.
2. Consent given by a caregiver older than 18 years.
3. Diagnosed with severe acute malnutrition (MUAC\&lt;115 mm, or WHZ ≤-3 or bipedal pitting edema).
4. Eligible for RUTF treatment (expanded below).

Exclusion Criteria:

1. Conditions preventing the child from receiving interventions, e.g., peanut butter allergy or cleft palate.
2. Moderate or severe disability which significantly affects normal child development (e.g., cerebral palsy or hydrocephalus), identified using a standardized screening form.
3. Children of families not living in the area or planning to move from the area within the follow-up period

Primary outcomes:
measure: Change in MDAT scores
timeFrame: Assessed at baseline, 12, 24 and 48 weeks
measure: Change in eye tracking scores
timeFrame: Baseline, 12, 24 and 48 weeks
Secondary outcomes:
measure: Level of caregiver stimulation and support
timeFrame: Assessed at baseline, 12, 24 and 48 weeks
measure: Fatty acid composition
timeFrame: at baseline and at week 12, and week 48
measure: Mid upper arm circumference (MUAC)
timeFrame: Baseline, weekly, 12, 24 and 48 weeks
measure: Mortality
timeFrame: 12, 24 and 48 weeks
measure: Process evaluation
timeFrame: Interviews will be conducted after the last PS session ( Week 11) , and where possible, again with the same caregivers at long term follow-up (week 24 and 48).
measure: Levels of choline
timeFrame: Baseline, 12, 24 and 48 weeks
measure: C-reactive protein (CRP)
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Ferritin
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Level of Alanine transaminase
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Level of Aspartate transaminase
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Level of maternal psychological distress
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Status of the learning environment
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Status of maternal social support framework
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Morbidity
timeFrame: 12, 24 and 48 weeks
measure: - Weight-for-height z-score (WHZ)
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Height-for-age z-score (HAZ) , based on length/height and age)
timeFrame: Baseline, 12, 24 and 48 weeks
measure: Rate of nutritional recovery at the end of intervention period
timeFrame: 12
measure: Proportion relapsing to moderate acute malnutrition (MAM) after recovery
timeFrame: 12 weeks
measure: Proportion relapsing to SAM after recovery
timeFrame: Any time point, 24 and 48 weeks
measure: Implementation evaluation
timeFrame: Interviews will be conducted after the last PS session ( Week 11) , and where possible, again with the same caregivers at long term follow-up (week 24 and 48).
Other outcomes:
Locations:
city: Mwanza
country: Tanzania
facility: National Institute for Medical Research
Study officials:
affiliation: Rigshospitalet, Denmark
name: Mette Olsen, MSc, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute for Medical Research
name: George PrayGod, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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