Clinical trial NCT06214897: Choline to Prevent SAM in Children With MAM
Official title: An Individually Randomized, Partially Blinded, Controlled Trial of Choline-containing Ready-to-use Supplementary Food (C-RUSF) for Children With Moderate Acute Malnutrition to Reduce Deterioration to Severe Acute Malnutrition Compared to Standard RUSF.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Moderate Acute Malnutrition
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Project Peanut Butter
name: Kamuzu University of Health Sciences
name: Balchem Corp
First posted: 2024-01-22
Enrollment: 1500
Sex: ALL
Minimum age (years): 6
Maximum age (years): 59
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to test choline supplementation in children with moderate acute malnutrition in Malawi. The main question it aims to answer is:

Will provision of RUSF with added choline (500mg/day) throughout treatment of moderate acute malnutrition (up to 12 weeks) reduce deterioration to severe acute malnutrition among 6-59 month old Malawian children compared with standard RUSF?

Detailed description: Moderate acute malnutrition (MAM) is common among children worldwide, with a prevalence of 50M and an annual incidence likely 3-5x this number. It is defined by mid-upper arm circumference (MUAC) ≥ 11.5 cm and \< 12.5 cm or weight-for-length (WLZ) z-score ≥ -3 and \< -2. MAM increases a child's risk of deterioration to severe acute malnutrition (SAM), stunting, death, infectious illnesses, and impaired cognitive development. In Malawi, in the year following MAM treatment, nearly one-third of children will face a repeat episode of MAM, 7-10% will develop SAM, and 4% will die. There is much progress yet to be made toward improving rates of recovery and preventing the worst outcomes for the millions of children suffering from MAM each year.

One potential avenue for improving outcomes in MAM is modification of supplementary foods used for its treatment. Choline is an essential nutrient for human health and development, evidence for which is largely drawn from animal models of choline deficiency in which various somatic and cognitive developmental abnormalities are found. Of the trials that have evaluated choline supplementation in humans, many have focused on the role of choline in brain development and, specifically, how it may help foster improved cognitive development in the setting of various insults, such as fetal alcohol syndrome.

There is also a growing body of evidence describing the many roles choline plays outside of the brain, including in the etiology of malnutrition. Recently, choline deficiency has been implicated in the development of kwashiorkor, an enigmatic form of severe acute malnutrition characterized by pitting edema, dermatitis, hair color changes, and fatty liver disease with inflammation. Animal models of choline deficiency display a remarkably similar phenotype to kwashiorkor. When choline has been given to mice, rats, and dogs with kwashiorkor-like malnutrition, the hallmark features of the disease have resolved. This line of evidence suggests a causal role for choline deficiency in kwashiorkor, proposed mechanisms for which include choline's functions in 1-carbon metabolism, sulfur amino acid recycling, and sparing of the essential amino acid methionine. Methionine is the key deficient amino acid in maize-predominant diets, such as are consumed in Malawi. Choline is most abundant in animal-source foods, precisely those which are lacking in the diets of many rural Malawian children. Kwashiorkor accounts for more than one-third of SAM in Malawi in children under 5 years of age and 80% of MAM deterioration to SAM. If the addition of choline to supplementary foods were demonstrated to reduce deterioration to SAM among children with MAM and thereby promote recovery, this would represent an important advance in MAM treatment.

Despite the data supporting choline's essential role in human health and emerging data on its potential therapeutic role in malnutrition, there are no specifications for choline content in food aid products. Common MAM treatment options, such as corn-soy-blend plus and RUSF contain 50-70mg choline, approximately one-third of the 150-200mg recommended for well children 6mo-3y of age. This does not account for the likely increased demand for choline in the setting of malnutrition.

This will be an individually randomized, investigator-blinded, controlled clinical trial. This trial will be conducted at 10 rural sites in southern Malawi where the co-Principal Investigator, Mark Manary, has run malnutrition treatment clinics for over 15 years. The study will include 1500 children (750 per group) 6-59 months of age with uncomplicated MAM, as defined by mid-upper arm circumference (MUAC) ≥ 11.5 cm and \< 12.5 cm and/or weight-for-length z-score (WLZ) ≥ -3 and \< -2. Exclusion criteria will be presence of nutritional edema, features of complicated MAM, such as mental status changes or breathing issues, as well as participation in a separate feeding program, known allergy to study food ingredient, intention to move away from catchment area within 3 months, developmental delay, or presence of a chronic severe medical condition such as congenital heart disease. Those who wish to take part will undergo randomization, wherein they will remove a single small opaque envelope from a larger opaque envelope and open it, revealing a colored sticker that will correspond to their study group. Caregivers will receive nutrition counselling, complete questionnaires pertaining to demographic, health history/symptoms, and socioeconomic information, and be provided with a two-week supply of their allotted study food for their child. Participants will receive approximately 500 Kcal/day of either C-RUSF or RUSF until they reach a clinical outcome (i.e., graduate, deteriorate to SAM, fail/remain MAM, transfer to hospital, death, default) or for a maximum of 12 weeks. They will be asked to return to clinic fortnightly for re-assessment of anthropometry, illness symptoms, and re-provision of supplementary food until they reach a study outcome. Participants will undergo MDAT testing at time of MAM outcome as well as 5-7 months after MAM outcome to undergo repeat MDAT testing. A randomly chosen subset of participants will undergo blood spot collection at time of MAM outcome.

Eligibility criteria: Inclusion Criteria:

* 6-59 months of age
* uncomplicated MAM (mid-upper arm circumference (MUAC) ≥ 11.5 cm and \< 12.5 cm and/or weight-for-length z-score (WLZ) ≥ -3 and \< -2)
* availability for the duration of the study with no plan to move from the catchment area of a participating clinic

Exclusion Criteria:

* presence of nutritional edema
* features of complicated MAM, such as mental status changes or breathing issues
* participation in another feeding program
* known allergy to study food ingredient
* intention to move away from catchment area within 9 months
* developmental delay
* presence of a chronic severe medical condition (other than TB or HIV) such as congenital heart disease

Primary outcomes:
measure: Percentage of pairwise comparisons with wins of Clinical Benefit, which is a composite of time-to-SAM, graduation, and rate of weight change between enrollment and 4-week follow-up.
timeFrame: 2-12 weeks of supplementary feeding
Secondary outcomes:
measure: Deterioration to SAM
timeFrame: 2-12 weeks of supplementary feeding
measure: Graduation
timeFrame: 2-12 weeks of supplementary feeding
measure: Rate of weight change
timeFrame: Across first 4 weeks of supplementary feeding
measure: Death
timeFrame: From enrollment to end of participant's engagement (at latest, time of 6-month post-outcome MDAT testing)
measure: Deterioration to kwashiorkor
timeFrame: 2-12 weeks of supplementary feeding
measure: Docosahexaenoic acid (DHA) status
timeFrame: 2-12 weeks of supplementary feeding (at time of MAM outcome)
measure: Malawi Developmental Assessment Tool global z-score
timeFrame: 6 months after MAM outcome
measure: Malawi Developmental Assessment Tool global z-score
timeFrame: Within 4 weeks of MAM outcome
measure: Rate of mid-upper arm circumference (MUAC) change
timeFrame: Across first 4 weeks of supplementary feeding
measure: Rate of length change
timeFrame: 2-12 weeks of supplementary feeding (until MAM outcome)
measure: Deterioration to marasmus
timeFrame: 2-12 weeks of supplementary feeding
measure: Change in MDAT global z-score
timeFrame: From MDAT near time of MAM outcome to 6-month post-MAM-outcome MDAT visit
measure: Malawi Developmental Assessment Tool gross motor sub-domain z-score
timeFrame: 6 months after MAM outcome
measure: Malawi Developmental Assessment Tool fine motor sub-domain z-score
timeFrame: 6 months after MAM outcome
measure: Malawi Developmental Assessment Tool language sub-domain z-score
timeFrame: 6 months after MAM outcome
measure: Malawi Developmental Assessment Tool social sub-domain z-score
timeFrame: 6 months after MAM outcome
measure: Malawi Developmental Assessment Tool gross motor sub-domain z-score
timeFrame: Within 4 weeks of MAM outcome
measure: Malawi Developmental Assessment Tool fine motor sub-domain z-score
timeFrame: Within 4 weeks of MAM outcome
measure: Malawi Developmental Assessment Tool language sub-domain z-score
timeFrame: Within 4 weeks of MAM outcome
measure: Malawi Developmental Assessment Tool social sub-domain z-score
timeFrame: Within 4 weeks of MAM outcome
measure: Diarrhea
timeFrame: 2-12 weeks of supplementary feeding (until MAM outcome)
measure: Proportion of participations requiring hospitalization
timeFrame: 2-12 weeks of supplementary feeding (until MAM outcome)
Other outcomes:
measure: MDAT global z-score by age
timeFrame: 6-month post-outcome MDAT visit
measure: MDAT global z-score by MAM outcome status
timeFrame: 6-month post-outcome MDAT visit
Locations:
city: Chikonde
country: Malawi
facility: Chikonde Health Center
city: Chipolonga
country: Malawi
facility: Chipolonga Health Center
city: Makhwira
country: Malawi
facility: Makhwira Health Center
city: Mbiza
country: Malawi
facility: Mbiza Health Clinic
city: Milonde
country: Malawi
facility: Milonde Health Center
city: Mitondo
country: Malawi
facility: Mitondo Health Center
city: Muloza
country: Malawi
facility: Muloza Health Clinic
city: Namasalima
country: Malawi
facility: Namasalima Health Center
city: Naphimba
country: Malawi
facility: Naphimba Health Center
city: Nkhate
country: Malawi
facility: Nkhate Health Clinic
Study officials:
affiliation: Washington University School of Medicine
name: Mark J Manary, MD
role: PRINCIPAL_INVESTIGATOR
References: