Clinical trial NCT06154174: Choline to Improve Malnutrition and Enhance Cognition
Official title: Choline to Improve Malnutrition and Enhance Cognition
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Severe Acute Malnutrition
Cognitive Impairment
Wasting
Kwashiorkor
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Project Peanut Butter
name: Kamuzu University of Health Sciences
name: Balchem Corporation
First posted: 2023-12-04
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 adding choline to ready-to-use therapeutic food (RUTF) in children with severe acute malnutrition (SAM) in Malawi. The main question it aims to answer is:

- Will the addition of a 500mg daily dose of choline to RUTF during treatment for SAM improve cognitive development among 6-59-month-old Malawian children compared with standard RUTF without added choline?

Detailed description: Severe acute malnutrition (SAM) affects approximately 14 million children worldwide at any one time and has an annual incidence of 3-5x this number. SAM is defined by wasting (mid-upper arm circumference \< 11.5 cm or weight-for-length z-score \< -3) or presence of bilateral pedal pitting edema. SAM increases short-term risks for infection, hospitalization, and death, as well as longer-term risks for stunted linear growth and impaired cognitive development. This lattermost consequence is increasingly recognized, with studies showing that children who have suffered from SAM score 2-3 standard deviations below age-expected norms on cognitive development tests.

Ready-to-use therapeutic food (RUTF) revolutionized SAM treatment by allowing it to occur in the home setting. RUTF cures most children with SAM and ameliorates many of its worst consequences. RUTF was designed to be food-safe and promote anthropometric recovery. Since its inception, evidence has accumulated suggesting that the original fatty acid content of RUTF was not optimized for cognitive recovery from SAM. A 2021 trial, the Improved PUFA Trial (PMID: 34726694), demonstrated that reducing the omega-6 fatty acid content of RUTF and adding docosahexaenoic acid (DHA) improved cognitive development 6 months after SAM treatment in Malawian children. It is possible that further modifications to RUTF's composition might promote greater cognitive recovery.

Choline is essential for human health and development and is recognized as such by the Institute of Medicine, which designates daily recommended intakes. Choline deficiency has been shown to induce a host of cognitive developmental problems in animal models, is associated with neural tube defects in humans, and mutations of choline transporters in humans yield developmental degenerative conditions which, while rare, shed light on the essential nature of choline in brain development. Several small randomized, controlled trials have shown benefits of choline supplementation during early life on child cognitive development, both in healthy children and in those exposed to insults such as in fetal alcohol syndrome.

Choline plays important roles in brain structure and function and is found primarily in animal-source foods, which are deficient in the diets of children with SAM. Choline is an essential component of the neuronal membrane as well as a precursor for acetylcholine, a key neurotransmitter. In addition, choline plays a role in the trafficking and cell membrane integration of DHA, which rapidly accumulates in the human brain during childhood and ultimately composes 40-50% of brain polyunsaturated fatty acids. Decades of findings from epidemiological studies and laboratory science, including with animal models, support the essential role of DHA in the structure and function of the brain and retina. The Improved PUFA Trial leveraged these insights and showed that the developing brain is sensitive to fatty acid intake in the context of SAM; providing DHA in RUTF improved brain development. Hepatic export of DHA into plasma and its target tissues, including the brain, relies in part on synthesis of phosphatidylcholine (PC) by phosphatidylethanolamine N-methyltransferase (PEMT). DHA-enriched PC molecules (PC-DHA) are generated by PEMT and exported for delivery throughout the body. Indeed, PEMT-deficient mice have reduced DHA plasma concentrations and pups born to PEMT-deficient dams have limited DHA brain accumulation. The PEMT pathway relies on adequate supply of dietary methyl donors such as choline. Pairing (1) choline's ability to increase DHA trafficking to/integration within the brain with (2) the power of DHA in SAM, it is possible that adding choline to RUTF containing DHA might promote cognitive recovery and development among malnourished children.

This will be an individually randomized, investigator/outcomes assessors/caregiver-blinded, controlled clinical trial designed to determine whether the addition of a daily dose of 500mg of choline to ready-to-use therapeutic food (C-RUTF) will improve cognitive development among Malawian children 6-59 months of age with SAM compared with standard RUTF (S-RUTF). This trial will be conducted at 10 rural sites in southern Malawi. 1500 children will be randomized 1:1 to receive 2 sachets per day of either C-RUTF or S-RUTF. Children will receive their allocated RUTF and return to clinic fortnightly for repeat anthropometric measurements, illness questions, and to receive more RUTF until they achieve a clinical outcome or for a maximum of 12 weeks, at which point they will undergo Malawi Developmental Assessment Tool (MDAT) testing and blood spot collection. Participants will be asked to return to clinic 5-7 months later for MDAT testing, the global z-score from which will be the trial's primary outcome.

Eligibility criteria: Inclusion Criteria:

* 6-59 months of age
* mid-upper arm circumference \< 11.5 cm and/or weight-for-length z-score \< -3 and/or presence of bilateral pedal pitting edema
* willingness to comply with all study procedures and availability for the duration of the study, including no plan to move from the catchment area of a participating clinic

Exclusion Criteria:

* features of complicated SAM: inability to tolerate a 30g test dose of RUTF, breathing difficulties, mental status changes, sepsis, or physician/nursing clinical assessment that the child needs immediate hospitalization
* participation in a separate feeding program within the past month
* known allergy to study food ingredient (peanut, milk, fish)
* intention to move away from catchment area within 9 months
* developmental delay
* presence of a chronic severe medical condition (other than TB and HIV), such as congenital heart disease

Primary outcomes:
measure: Malawi Developmental Assessment Tool global z-score
timeFrame: 6 months after SAM outcome
Secondary outcomes:
measure: Malawi Developmental Assessment Tool gross motor sub-domain z-score
timeFrame: 6 months after SAM outcome
measure: Malawi Developmental Assessment Tool fine motor sub-domain z-score
timeFrame: 6 months after SAM outcome
measure: Malawi Developmental Assessment Tool language sub-domain z-score
timeFrame: 6 months after SAM outcome
measure: Malawi Developmental Assessment Tool social sub-domain z-score
timeFrame: 6 months after SAM outcome
measure: Malawi Developmental Assessment Tool global z-score
timeFrame: Within 1 month of SAM outcome
measure: Malawi Developmental Assessment Tool gross motor sub-domain z-score
timeFrame: Within 1 month of SAM outcome
measure: Malawi Developmental Assessment Tool fine motor sub-domain z-score
timeFrame: Within 1 month of SAM outcome
measure: Malawi Developmental Assessment Tool language sub-domain z-score
timeFrame: Within 1 month of SAM outcome
measure: Malawi Developmental Assessment Tool social sub-domain z-score
timeFrame: Within 1 month of SAM outcome
measure: Recovery
timeFrame: 2-12 weeks of therapeutic feeding
measure: DHA status
timeFrame: 2-12 weeks of therapeutic feeding (until SAM outcome)
measure: Time-to-recovery
timeFrame: 2-12 weeks of therapeutic feeding
measure: Proportion of participants who die
timeFrame: 2-12 weeks of therapeutic feeding
measure: Proportion of participants who die
timeFrame: From enrollment to study end (6-month post-SAM-outcome MDAT visit)
measure: Proportion of participants remaining with SAM
timeFrame: After 12 weeks of therapeutic feeding
measure: Proportion of participants with kwashiorkor resolution
timeFrame: 2-12 weeks of therapeutic feeding
measure: Time-to-kwashiorkor resolution
timeFrame: 2-12 weeks of therapeutic feeding
measure: Rate of weight gain
timeFrame: 2-12 weeks of therapeutic feeding (until SAM outcome)
measure: Rate of length gain
timeFrame: 2-12 weeks of therapeutic feeding (until SAM outcome)
measure: Proportion of participants with recurrence of SAM
timeFrame: From recovery until study end (6-month post-SAM-outcome MDAT visit)
measure: Change in MDAT global z-score
timeFrame: From MDAT near time of SAM outcome to 6-month post-SAM-outcome MDAT visit
measure: Proportion of participations requiring hospitalization
timeFrame: Enrollment to 6-month post-SAM-outcome MDAT visit)
measure: Diarrhea
timeFrame: 2-12 weeks of therapeutic feeding (until SAM outcome)
Other outcomes:
measure: MDAT global z-score by age
timeFrame: 6-month post-outcome MDAT visit
measure: MDAT global z-score by SAM outcome status
timeFrame: 6-month post-outcome MDAT visit
Locations:
city: Makhwira
country: Malawi
facility: Makhwira
state: Chikwawa
city: Mitondo
country: Malawi
facility: Mitondo
state: Chikwawa
city: Nkhate
country: Malawi
facility: Nkhate
state: Chikwawa
city: Chipolonga
country: Malawi
facility: Chipolonga
state: Machinga
city: Chikonde
country: Malawi
facility: Chikonde
state: Mulanje
city: Mbiza
country: Malawi
facility: Mbiza
state: Mulanje
city: Milonde
country: Malawi
facility: Milonde
state: Mulanje
city: Muloza
country: Malawi
facility: Muloza
state: Mulanje
city: Namasalima
country: Malawi
facility: Namasalima
state: Mulanje
city: Naphimba
country: Malawi
facility: Naphimba
state: Mulanje
Study officials:
affiliation: Washington University School of Medicine
name: Mark J Manary, MD
role: PRINCIPAL_INVESTIGATOR
References: