Choline to Prevent SAM in Children With MAM

Moderate Acute Malnutrition Clinical Trial

— CHOP-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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06214897
• Other study ID #: 202308159
• Status: Recruiting
• Phase: N/A
• Start date: March 18, 2024
• Est. completion date: February 2026

Study information

• Verified date: May 2024
• Source: Washington University School of Medicine
• Contact: Mark J Manary, MD
• Phone: 314-454-2178
• Email: manarymj[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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?

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1500
• Est. completion date: February 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 59 Months

Eligibility

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

Related Conditions & MeSH terms

• Malnutrition
• Moderate Acute Malnutrition

Intervention

Dietary Supplement:
• C-RUSF (Ready-to-use Supplemental Food with added Choline)
Ready-to-use Supplemental Food with added Choline
• S-RUSF (Ready-to-use Supplemental Food without added Choline)
Standard Ready-to-use Supplemental Food

Locations

Country	Name	City	State
Malawi	Chikonde Health Center	Chikonde
Malawi	Chipolonga Health Center	Chipolonga
Malawi	Makhwira Health Center	Makhwira
Malawi	Mbiza Health Clinic	Mbiza
Malawi	Milonde Health Center	Milonde
Malawi	Mitondo Health Center	Mitondo
Malawi	Muloza Health Clinic	Muloza
Malawi	Namasalima Health Center	Namasalima
Malawi	Naphimba Health Center	Naphimba
Malawi	Nkhate Health Clinic	Nkhate

Sponsors (4)

Lead Sponsor	Collaborator
Washington University School of Medicine	Balchem Corp, Kamuzu University of Health Sciences, Project Peanut Butter

Country where clinical trial is conducted

Malawi, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	MDAT global z-score by age	Subgroups: enrollment <12 vs. >=12 months of age, -6 to +6, higher scores are better	6-month post-outcome MDAT visit
Other	MDAT global z-score by MAM outcome status	Subgroups: Recovered vs. Other, -6 to +6, higher scores are better	6-month post-outcome MDAT visit
Primary	Percentage of pairwise comparisons with wins of Clinical Benefit, which is a composite of time-to-SAM, time-to-graduation, and rate of weight change between enrollment and 4-week follow-up.	Clinical benefit is defined as a composite of time-to-SAM, time-to-graduation, and rate of weight change. Each participant randomized to C-RUSF is compared to each participant randomized to S-RUSF. For any two participants, a participant will win, i.e. achieve a better clinical outcome, as determined by assessing the following criteria sequentially, stopping when an advantage for either participant is shown: Time-to-SAM: developing SAM faster is worse than slower; tied if not possible to determine.; Time-to-graduation: faster graduation is better than slower graduation; tied if not possible to determine.; Rate of weight change: more positive rate of weight change is better. Rate of weight change is difference in weight (g) between the second follow-up visit and the enrollment visit, divided by enrollment weight (kg), divided by the (d) time elapsed between visits. If the participant lacks data beyond the first follow-up visit, this data will be used instead.	2-12 weeks of supplementary feeding
Secondary	Deterioration to SAM	Children who meet any criteria for SAM during MAM treatment will be considered to have deteriorated to SAM. These are: mid-upper arm circumference (MUAC) < 11.5 cm; weight-for-length z-score (WLZ) < -3; Presence of bilateral pitting edema	2-12 weeks of supplementary feeding
Secondary	Graduation	Based on the criteria by which the participant was diagnosed with MAM: If a child qualifies for the study based on MUAC < 12.5 cm, the child must obtain MUAC = 12.5 cm.; If a child qualifies for the study based on WLZ < -2, the child must obtain WLZ = -2.; If a child has MUAC < 12.5 cm and WLZ < -2, either MUAC = 12.5 cm or WLZ = -2 is required for graduation	2-12 weeks of supplementary feeding
Secondary	Rate of weight change	g/kg/day. Rate of weight gain is calculated as difference in weight in grams between the second follow-up visit (usually 4 weeks after enrollment) and the enrollment visit, divided by enrollment weight (kg), divided by the time between the second follow-up visit and enrollment visit. If the participant lacks data beyond the first follow-up visit, this data will be used instead of the second follow-up visit data. Participants without a follow-up visit will not have data available for rate of weight gain.	Across first 4 weeks of supplementary feeding
Secondary	Death	Defined by caregiver report	From enrollment to end of participant's engagement (at latest, time of 6-month post-outcome MDAT testing)
Secondary	Deterioration to kwashiorkor	Development of nutritional edema (bilateral pedal pitting edema)	2-12 weeks of supplementary feeding
Secondary	Docosahexaenoic acid (DHA) status	DHA as % of serum fatty acids	2-12 weeks of supplementary feeding (at time of MAM outcome)
Secondary	Malawi Developmental Assessment Tool global z-score	Age-standardized score, -6 to +6, higher scores are better	6 months after MAM outcome
Secondary	Malawi Developmental Assessment Tool global z-score	Age-standardized score, -6 to +6, higher scores are better	Within 4 weeks of MAM outcome
Secondary	Rate of mid-upper arm circumference (MUAC) change	mm/week	Across first 4 weeks of supplementary feeding
Secondary	Rate of length change	mm/week	2-12 weeks of supplementary feeding (until MAM outcome)
Secondary	Deterioration to marasmus	Development of MUAC < 11.5 cm and/or WLZ < -3	2-12 weeks of supplementary feeding
Secondary	Change in MDAT global z-score	Difference in MDAT global z-score between 6-month post-MAM outcome visit and MDAT global z-score measured within 4 weeks of MAM outcome, more positive scores are better	From MDAT near time of MAM outcome to 6-month post-MAM-outcome MDAT visit
Secondary	Malawi Developmental Assessment Tool gross motor sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	6 months after MAM outcome
Secondary	Malawi Developmental Assessment Tool fine motor sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	6 months after MAM outcome
Secondary	Malawi Developmental Assessment Tool language sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	6 months after MAM outcome
Secondary	Malawi Developmental Assessment Tool social sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	6 months after MAM outcome
Secondary	Malawi Developmental Assessment Tool gross motor sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	Within 4 weeks of MAM outcome
Secondary	Malawi Developmental Assessment Tool fine motor sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	Within 4 weeks of MAM outcome
Secondary	Malawi Developmental Assessment Tool language sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	Within 4 weeks of MAM outcome
Secondary	Malawi Developmental Assessment Tool social sub-domain z-score	Age-standardized score, -6 to +6, higher scores are better	Within 4 weeks of MAM outcome
Secondary	Diarrhea	Days, reported by caregiver, safety outcome	2-12 weeks of supplementary feeding (until MAM outcome)
Secondary	Proportion of participations requiring hospitalization	Safety outcome	2-12 weeks of supplementary feeding (until MAM outcome)