Safety Trial of F-60 Among Children Hospitalized With SAM

International Centre for Diarrhoeal Disease Research (icddr,b)

Status: Invitation-only

Conditions: Dietary Supplementation; Children; Severe Acute Malnutrition

Treatments: Dietary Supplement: F75 milk feeds; Dietary Supplement: F60 milk feeds

Study type: Interventional

Funder types: Other

Identifiers

NCT07752628

PR- 25-014

Details and patient eligibility

About

The current WHO-recommended F-75 diet for stabilization of SAM has remained largely unchanged since its development in the 1990s. No clinical trial has studied enhanced therapeutic formulas during the stabilization phase, particularly in high-burden, low-resource settings. Additionally, the current F75 nutritional formula was based only on expert opinion, not scientific evidence.

Evidence suggests that modifying the nutrient profile of stabilization formulas may improve survival, reduce complications such as refeeding syndrome, and enhance early recovery. A better stabilization formula for these medically fragile children has the potential to reduce mortality. The purpose of this randomized controlled clinical trial (RCT) is to test the hypothesis that an enhanced nutrient fortified therapeutic stabilization formula (F-60) will improve outcomes for children hospitalized with SAM, relative to the current standard of care (F-75).

Hypothesis: The main hypothesis of this safety study is that F-60 is not inferior to F-75.

Objectives:

To test this hypothesis, Investigators will pursue two specific aims. Aim 1: to assess laboratory outcomes in children stabilized with F-60. Aim 2: to assess clinical outcomes in children who receive F-60.

Full description

Outcomes for children with SAM have improved over the past 20 years. Community-based treatment programs and RUTF are making an impact. However, outcomes lag for hospitalized children with SAM. In many settings, more than 10% of these children die. Inpatient outcomes for children with SAM may be improved by more precisely matching the nutritional composition of the formula that is provided during stabilization to the unique nutritional requirements of children hospitalized with SAM. Specifically, modifying the nutrient profile of stabilization formula may reduce mortality, by reducing risk for complications such as refeeding syndrome, while supporting earlier recovery.

Therapeutic formulas for treating SAM were developed gradually, over the course of several decades. A basic goal of stabilizing care is to limit subsequent risk for refeeding syndrome, which occurs most often when the extra energy and protein needed for catch-up growth are introduced. The current standard of care stabilization formula, F-75, was developed to replenish electrolytes and to correct metabolic abnormalities. F-75 was formalized by WHO in 1999. Since then, widening access to community-based treatment programs for SAM has altered patient volume and acuity on malnutrition wards. Fewer children are now hospitalized for SAM. However, the total global requirement for for F-75 continues to grow, with stockouts now increasingly frequent.This may be partly due to increased acuity and length of stay among children with SAM who need hospitalization. An improved stabilization formula has the potential to improve outcomes for these medically fragile children, while also reducing costs by shortening the average length of stay.

F-60 is a novel therapeutic formula intended, like F-75, for children with SAM who need inpatient stabilization. Data on the energy requirements and optimal nutrient composition of therapeutic feeds have remained limited since their original development in the 1980s-1990s. The nutritional profile of F-60 reflects recent clinical evidence and regulatory guidance ensuring consistency with the most current scientific and regulatory recommendations. F-60 contains less energy (60 kcal/100ml) than F-75 (77 kcal/100ml). F-60 also contains greater concentrations of particular vitamins, minerals, methyl donors, and amino acids. From a regulatory standpoint, F-60 is a 'formula for special medical purposes'. It has not yet been tested in children. In this respect, F-60 is an investigational product. Much has been learned about malnutrition since F-75 was conceptualized more than 40 years ago. In developed settings, strategies to prevent refeeding syndrome are now increasingly nuanced. The design of F-60 reflects these recent insights, including one-carbon dysfunction, intestinal barrier dysfunction, metabolic recovery and risk of refeeding syndrome.

The trial proposed here aims to assess the biochemical and clinical safety of F-60, relative to the current standard of care, F-75.

The nutrient profile of F-60 has been meticulously formulated for this trial. F-60 contains less energy than F-75, which provides 77 kcal/100 ml, exceeding the Codex maximum of 70 kcal/100 ml. (8) Total energy content of F-60 reflects the Codex minimum (60 kcal/100 ml). This change aims to match the measured median resting energy expenditure in most children with SAM (≈78 kcal/kg/day). The reduction of energy in F-60 is achieved mainly by reducing the carbohydrate content. F-60 is fortified with essential amino acids. F-60 contains more milk protein and five essential amino acids that are particularly limiting in the diets that are associated with SAM: lysine, methionine, cysteine, threonine, and tryptophan. F-60 contains greater concentrations of certain electrolytes relative to F-75. These changes are intended to reduce the risk of cardiac conduction disturbances by more quickly repleting diminished electrolyte stores, a frequent occurrence in SAM. Potassium deficiency is common in SAM. Potassium is increased in F-60. F-75 contains 145 mg of potassium per 100 ml. F-60 provides 200 mg per 100 ml. The total phosphorus content of F-60 is comparable, providing ~ 117 mg/kg/day. The increased phosphorous content of F-75 is designed to more effectively replenish phosphorus stores. Magnesium depletion increases risk for cardiac arrhythmias during refeeding. F-60 provides more magnesium (23.4 mg/kg/day) than F-75 (12.3 mg/kg/day), when children are treated with a standard feed volume (ie, 130 ml/kg/day). F-60 incorporates modest trace mineral adjustments. These changes aim to ensure comparable intake between children consuming F-75 and F-60. Some moderate increases in F-60 reflect the greater inclusion of milk powder in F-60, which contains multiple trace minerals. F-60 provides increased amounts of water-soluble vitamins; B vitamins and vitamin C. These changes aim to support quicker metabolic recovery during stabilization. Thiamine (B1) is increased in F-60. Acute thiamine deficiency causes severe morbidity. Riboflavin (B2) is increased in F-60. Riboflavin supports energy metabolism and plays a vital role in one-carbon movement by supporting folate regeneration. Vitamin B3 (nicotinamide) is increased in F-60. B3 content in F-60 is increased to levels shown to support immune function. Pantothenic Acid (B5) is increased in F-60. Pantothenic acid is required for the synthesis of coenzyme A and acyl carrier protein. Both are essential for lipid metabolism. Pyridoxine (B6) is increased in F-60, providing ~0.32 mg/kg/day. Biotin (B7) is increased in F-60. Biotin is a coenzyme for carboxylases involved in fatty acid metabolism and keratin synthesis. Folate (B9) is increased in F-60. Folate is essential for one-carbon metabolism. It supports the transfer of methyl groups in the folate cycle. Cobalamin (B12) is increased in F-60: It supports two key enzymes: methylmalonyl-CoA mutase and methionine synthase, both essential for energy metabolism and one-carbon flux. Vitamin C is increased in F-60. Children who develop SAM often consume diets largely devoid of fresh fruits and vegetables, containing limited amounts of vitamin C. F-75 contains fat-soluble vitamins at levels adequate for age-specific nutritional requirements. F-60 preserves this standard for vitamins A, D, and E, with adjustments limited to ensuring intake that is comparable with F-75. In contrast, vitamin K content is increased in F-60. Carnitine, inositol, and taurine supplemented in F60 according to to current Codex Alimentarius guidelines. Choline is increased in F-60. The additional choline in F-60 aims to support cell membrane renewal, one-carbon function, and efficient energy metabolism during stabilization of SAM.

Enrollment: 320 estimated patients

Sex: All

Ages: 6 to 59 months old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age 6 to 59 months.
• Severe Acute Malnutrition (WHZ <-3 z-scores of the median WHO growth standards and/or MUAC <11.5 cm or bilateral pitting nutritional edema).
• Received a maximum of 2 feeds of F75 (or milk suzi) at the time of enrolment.
• Primary caregiver is able to provide written or witnessed informed consent.

Exclusion criteria

• Congenital heart disease
• A known or suspected diagnosis of tuberculosis at the time of screening
• Anatomic abnormalities of the gastrointestinal tract
• Cancer
• Spastic cerebral palsy, hydrocephalus,
• Haemoglobinopathies.
• Children weigh more than 16 kg
• Diarrhea lasting more than 14 days prior to hospitalization.
• Children who require invasive critical care (ie, mechanical ventilation, continuous positive airway pressure (CPAP) >5 cm H2O, or >1 inotrope for BP support) will be ineligible. Informed written consent will be obtained from the child's guardian, following local practices.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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320 participants in 2 patient groups

F75 milk feeds

Active Comparator group

Description:

The WHO endorsed a standardized formulation of F-75 in the 1990s and energy density is 77 kcal/100ml. F75 aims to provide 95 kcal/kg/day and was intended to support children through early stabilization when fighting infections and is not aimed at weight gain.

Treatment:

Dietary Supplement: F75 milk feeds

F60 milk feeds

Experimental group

Description:

F-60 contains an energy density of 60 kcal/100ml. F-60 also contains greater concentrations of particular vitamins, minerals, methyl donors, and amino acids.

Treatment:

Dietary Supplement: F60 milk feeds