Proof-of-concept study of the efficacy of a microbiota-directed complementary food formulation (MDCF) for treating moderate acute malnutrition.

BACKGROUND: Childhood undernutrition remains a significant global health challenge accounting for over half of all under 5 child mortality. Moderate acute malnutrition (MAM), which leads to wasting [weight-for-length z-scores (WLZ) between - 2 and - 3], affects 33 million children under 5 globally and more than 2 million in Bangladesh alone. We have previously reported that acute malnutrition in this population is associated with gut microbiota immaturity, and in a small, 1-month pre-proof-of-concept (POC) study demonstrated that a microbiota-directed complementary food formulation (MDCF-2) was able to repair this immaturity, promote weight gain and increase plasma biomarkers and mediators of healthy growth. Here we describe the design controlled feeding study that tests whether MDCF-2 exhibits superior efficacy (ponderal growth, host biomarkers of a biological state) than a conventional Ready-to-use Supplementary Food (RUSF) in children with MAM over intervention period of 3 months. METHODS: Two separate cohorts of 12-18-month-old children will be enrolled: 124 with primary MAM, and 124 with MAM after having been treated for severe acute malnutrition (post-SAM MAM). We have established several field sites in an urban slum located in the Mirpur district of Dhaka, Bangladesh and at a rural site, Kurigram in the north of Bangladesh. The two groups of children receiving MDCF-2 and RUSF will be compared at baseline (pre-intervention), after 1 month, at the end of intervention (3 months), 1 month after cessation of intervention, and every 6 months thereafter for 4 years. DISCUSSION: This study will determine whether daily, controlled administration of MDCF-2 for 3 months provides superior improvements in weight gain, microbiota repair, and elevated levels of key plasma biomarkers/mediators of healthy growth compared to the control RUSF formulation. The pathogenesis of MAM is poorly defined and there are currently no WHO-approved treatments; results from the current study of children with primary MAM and post-SAM MAM will shed light on the effects of the gut microbiota on childhood growth/development and will provide a knowledge base that may help improve complementary feeding practices. TRIAL REGISTRATION: The primary MAM and post-SAM MAM trials are registered in Clintrials.gov (NCT04015999 and NCT04015986, registered on July 11, 2019, retrospectively registered).

Effect of a newly developed ready-to-use supplementary food on growth indicators in children with mild to moderate malnutrition.

OBJECTIVES: Malnutrition is one of the leading causes of death among children younger than five years. In this study, we aimed to formulate a ready-to-use supplementary food (RUSF), based on local food products, and investigate its efficacy on growth indicators in children with mild to moderate malnutrition. STUDY DESIGN: This is a randomized controlled clinical trial. METHODS: This study was performed in six health centers in Shahr-e-Rey, Tehran, Iran, between April and October 2017. One hundred children, aged 24-59 months, with mild to moderate malnutrition (weight-for-height Z-score [WHZ] between -3 and -1) were randomly assigned to two groups to receive either 1-3 sachets of RUSF or normal diet for 8 weeks. All mothers and caregivers received nutrition education. Growth indicators including weight and height, WHZ, and body mass index (BMI), along with clinical outcomes, were assessed. RESULTS: Children who received RUSF had a significant increase in weight (1.44 ± 0.38 vs 0.7 ± 0.32 kg, respectively, P < 0.001), and BMI (1.2 ± 0.47 vs 0.35 ± 0.33 kg/m2, respectively, P < 0.001) compared with the control group. There was a greater daily weight gain during the first 4 weeks (P < 0.001) and throughout the study (P = 0.013) in the RUSF group. Daily height gain was considerably higher in the RUSF group during the first 4 weeks (P = 0.027). Children in the RUSF group had more improvement in WHZ (1.18 ± 0.41 vs 0.41 ± 0.31, P < 0.001) after supplementation. Besides, 92% of the RUSF and 12% of the control group reached to WHZ > -1 at the end of the study (P < 0.001). There was lower prevalence of diarrhea (12% vs 28.6%, respectively, P = 0.01) and marginally lower fever (16% vs 36.7%, respectively, P = 0.05) in the intervention than in the control group. CONCLUSIONS: A newly developed RUSF improved growth indicators and clinical outcomes in children with mild to moderate malnutrition. CLINICAL TRIAL REGISTRY NUMBER: IRCT2017021315536N6 (registered at www.irct.ir).

Effectiveness of a locally produced ready-to-use supplementary food in preventing growth faltering for children under 2 years in Cambodia: a cluster randomised controlled trial.

This cluster randomised controlled trial tested the effectiveness of a locally produced, fish-based, ready-to-use supplementary food (RUSF) to prevent growth faltering (decline in z-scores). Cambodian infants (n= 485), aged 6 to 11 months, were randomised by site to receive the RUSF, Corn-Soy Blend++ (CSB++), micronutrient powders (MNP), or no supplement (control). The intervention was for 6 months. In unadjusted analysis, the control group had statistically significantly decreased weight-for-age z-scores (WAZ; -0.02, 95%CI = -0.03 - -0.01, P= 0.001) and height-for-age z-scores (HAZ; -0.07, 95%CI = -0.09 - -0.05, P < 0.001), and increased mid-upper arm-circumference (MUAC; 0.02cm, 95%CI = 0.01 - 0.04, P = 0.010), but no statistically significant change in weight-for-height z-scores (WHZ). The RUSF group did not differ significantly from the control for WAZ, HAZ or WHZ (in other words, WAZ and HAZ decreased and WHZ did not change), but had increased MUAC in comparison to the control (0.04cm, 95%CI = 0.01 - 0.06, P = 0.008). There were no statistically significant differences between the RUSF group and the CSB++ or MNP groups with respect to WAZ, HAZ, WHZ or MUAC. Interestingly, in adjusted analysis, low consumers of RUSF had increased WAZ, WHZ and MUAC (0.03, 95%CI = 0.01-0.06, P = 0.006; 0.04, 95%CI = 0.01-0.08, P = 0.026; and 0.05cm, 95%CI = 0.02-0.09, P = 0.004, respectively) compared with the control. The novel RUSF, particularly in small quantities, protected against ponderal growth faltering, but the improvements were of limited clinical significance.

Development and testing of locally-produced ready-to-use therapeutic and supplementary foods (RUTFs and RUSFs) in Cambodia: lessons learned.

BACKGROUND: Rates of childhood undernutrition are persistently high in Cambodia. Existing ready-to-use supplementary and therapeutic foods (RUSFs and RUTFs) have had limited acceptance and effectiveness. Therefore, our project developed and trialled a locally-produced, multiple micronutrient fortified lipid-based nutrient supplement (LNS) with therapeutic and supplementary versions. This ready-to-use food (RUF) is innovative in that, unlike many RUFs, it contains fish instead of milk. Development began in 2013 and the RUF was finalised in 2015. From 2015 until the present, both the RUTF and the RUSF versions were trialled for acceptability and effectiveness. METHODS: This paper draws on project implementation records and semi-structured interviews to describe the partnership between the Cambodian Ministries of Health and Agriculture, Forestry and Fisheries, UNICEF, the French National Research Institute for Sustainable Development (IRD), universities, and Vissot factory. It discusses the project implementation and lessons learned from the development and trialling process, and insights into positioning nutrition on the health agenda in low and middle-income countries. RESULTS: The lessons learned relate to the importance of project planning, management, and documentation in order to seize opportunities in the research, policy, advocacy, and programming environment while ensuring adequate day-to-day project administration and resourcing. CONCLUSIONS: We conclude that projects such as ours, that collaborate to develop and test novel, locally-produced RUTFs and RUSFs, offer an exciting opportunity to respond to both local programmatic and broader research needs.

Acceptability of locally-produced Ready-to-Use Supplementary Food (RUSF) for children under two years in Cambodia: A cluster randomised trial.

In Cambodia, existing food products for treating or preventing undernutrition have met with limited success. Therefore, in 2014, alternative ready-to-use foods were developed. This trial aimed to assess the acceptability of the novel ready-to-use supplementary food (RUSF) as a snack or mixed with borbor (white rice porridge), compared with corn-soy blend plus plus (CSB++) and borbor fortified with micronutrient powder (MNP). The nonblinded, randomised 4 × 4 crossover trial recruited 95 children aged 9-23 months from communities in peri-urban Phnom Penh. Small quantities (100 g for porridges, 42 g for snack) of each food were offered for three consecutive days at testing sites (homes of health volunteers). Main outcomes were children's consumption, caregivers' assessment of children's preferences, and caregivers' ranking of the foods. Median percentage consumed of the test food servings ranged from 21 to 50% (p = 0.003). The odds of children consuming over 50% were greatest for borbor fortified with MNP versus RUSF snack (unadjusted OR = 6.79, CI = 2.80-16.47, p < 0.001). However, the median energy children received when consuming the RUSF with borbor (57 kcals) or as a snack (48 kcals) was greater than with CSB++ (15 kcals) or borbor fortified with MNP (18 kcals; p < 0.001). Therefore, although children ate less RUSF, it provided approximately three times more kilocalories. Caregivers reported that their children had the highest preference for borbor fortified with MNP. Caregivers themselves ranked the novel RUSF snack highest. Thus, the innovative RUSF was considered sufficiently acceptable to proceed to an effectiveness trial.

Randomised controlled trial to test the effectiveness of a locally-produced ready-to-use supplementary food (RUSF) in preventing growth faltering and improving micronutrient status for children under two years in Cambodia: a study protocol.

BACKGROUND: Existing ready-to-use supplementary and therapeutic foods (RUSFs and RUTFs) have had limited acceptance and effectiveness in Cambodia. This has hampered the treatment and prevention of child malnutrition. An innovative, locally produced, multiple micronutrient fortified lipid-based nutrient supplement (LNS) has been developed for use as an RUSF. Unlike most RUSFs, which contain milk, this product contains fish as the animal protein. Few RUSFs have been formulated using non-milk animal-source foods and they have not been widely tested. An acceptability trial that was conducted on this novel RUSF in June 2015 demonstrated that children will eat the RUSF and that caregivers will feed it to their children. The current trial aims to evaluate the effectiveness of the RUSF in preventing growth faltering and improving micronutrient status in Cambodian children. METHODS AND ANALYSIS: This trial is a six-month, prospective, cluster randomised, non-blinded controlled trial among infants in peri-urban Phnom Penh. The trial aims to establish the superiority of the novel RUSF, compared to three alternatives (Corn-Soy Blend Plus Plus (CSB++) and Sprinkles micronutrient powders as active comparators, and the unimproved diet as a control). The allocation ratio is 1:1. Healthy children (N = 540) aged six to eleven months will be recruited. Data will be collected at baseline, and monthly thereafter for a period of six months. Participants will be provided with a monthly supply of the food to which their village has been allocated. DISCUSSION: There is an urgent need to develop locally produced and culturally acceptable RUSFs, and to compare these with existing options in terms of their potential for preventing malnutrition, in Cambodia and elsewhere. This trial will contribute much-needed data on the effectiveness of supplementary foods with an animal-source food other than milk, by comparing a novel RUSF based on fish to one that uses milk (CSB++). Moreover, it will deepen the understanding of the impact of multiple micronutrients provided with or without macronutrients, by comparing the novel RUSF and CSB++, which combine macronutrients with multiple micronutrients, to Sprinkles, which contains no macronutrients. In addition, it will augment the body of evidence from Asia. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: LNS-CAMB-INFANTS-EFF; NCT02257762 .

Crossover trial to test the acceptability of a locally produced lipid-based nutrient supplement (LNS) for children under 2 years in Cambodia: a study protocol.

INTRODUCTION: The acceptability and efficacy of existing ready-to-use supplementary and therapeutic foods has been low in Cambodia, thus limiting success in preventing and treating malnutrition among Cambodian children. In that context, UNICEF and IRD have developed a locally produced, multiple micronutrient fortified lipid-based nutrient supplement. This food is innovative, in that it uses fish instead of milk as the animal source food. Very few supplementary foods have non-milk animal source foods, and in addition they have not been widely tested. This trial will assess the novel food's acceptability to children and caregivers. METHODS AND ANALYSIS: This is a cluster-randomised, incomplete block, 4×4 crossover design with no blinding. It will take place in four sites in a community setting in periurban Phnom Penh. Healthy children aged 9-23 months (n=100) will eat each of four foods for 3 days at a time. The amount they consume will be measured, and at the end of each 3-day set, caregivers will assess how well their child liked the food. After 12 days, caregivers themselves will do a sensory test of the 4 foods and will rank them in terms of preference. ETHICS AND DISSEMINATION: Ethical clearance was received from the University of Queensland Medical Research Ethics Committee (2014001070) and from Cambodia's National Ethics Committee for Health Research (03/8 NECHR). REGISTRATION: ClinicalTrials.gov, identifier: LNS-CAMB-INFANTS; NCT02257437. Pre-results.