Efficacy of a Nutrient Blend in Improving Neurocognitive and Behavioral Outcomes in Infants: a Randomized, Controlled, Intervention Study

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the efficacy of the nutrient blend in a starter infant formula (IF) and follow up infant formula (FUF) in improving the neurocognitive and behavioural outcomes among formula-fed infants randomized to the experimental formula (EF) versus the control formula (CF).

Detailed Description
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This is a prospective, randomized, controlled, double-blind, 2-arm parallel-group clinical trial in the Philippines. Subjects will be recruited from a single centre; in case of insufficient recruitment, more sites will be added to the study. The clinical trial is composed of two parts: a double-blind interventional period and a follow-up period. The first period is the double-blind intervention phase from enrolment (V1) until age 12 months (V5). The intervention will be provided only during this double-blind phase. The second period is a non-interventional follow-up period from age 12 months until age 24 months.

Official Title
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Efficacy of a Nutrient Blend Comprised of Specific Nutrients in Improving Neurocognitive and Behavioural Outcomes in Infants: a Randomized, Controlled, Intervention Study

Conditions
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Infant Nutrition, Cognitive Development

Intervention / Treatment
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* Other: Experimental formula
* Other: Control Formula


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants between 45 to 60 days of age at enrolment Infant's ≥ 37 completed weeks of gestation, with a birth weight of ≥ 2.5 kg and ≤ 4.5 kg and singleton born. Infants generally healthy at birth with an Apgar score ≥7 at 5 min Exclusively formula fed for at least 14 days before randomization and the choice of formula feeding has been taken by the parents before the beginning of the trial Signed informed consent obtained for infant's and parents' participation in the study Parents of infant agree not to enrol infant in another interventional clinical research study while participating in this study Parent of infant agrees to provide to their infants the study formula and not replace it with another commercial formula. Parent of the infant is of legal age of consent, must understand the informed consent form and other study documents, willing and able to fulfil the requirements of the study protocol. Parent of infant can be contacted directly by telephone or email throughout the study. Exclusion Criteria: History of underlying metabolic or chronic disease; congenital malformation; or any other condition which, in the opinion of the investigator, is likely to interfere with: the ability of the infant to ingest food, the normal growth and development of the infant, or the evaluation of the infant. Evidence of feeding difficulties or formula intolerance, such as vomiting or poor intake, at time of randomization (at investigator discretion) Infants with known or suspected intolerance to cow milk infant formula or allergy The infant is identified to have a chromosomal or major congenital anomaly or significant medical and/or genetic conditions that interferes with adequate functioning in daily life or likely to interfere with normal growth and development or with the normal maturation of visual or cognitive function (including visual/hearing impairment), known head or brain disease, injury such as microcephaly or macrocephaly, immunocompromised or suffered from significant illness, developmental delay or disability Infants who have been adopted or are foster infants Infants born to mothers with chronic illness, such as HIV disease, renal or hepatic disease, type 1 or type 2 diabetes, alcoholism, or substance abuse Presence of a first degree relative with neurologic or psychiatric diseases (e.g., attention deficit hyperactivity disorder, autism, behavioural problems, bipolar disorder, depression, intellectual disability, or schizophrenia).

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 8 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Powdered cow's milk-based infant formula containing uniquely processed whey protein<br>Starter and follow up formula containing combination of an HMO blend, myelin nutrient blend, and MOS | Other: Experimental formula<br>* Cow's milk-based infant formula with a specific blend of nutrients at pre-defined levels<br>|
| Active Comparator: Powdered infant fortified cow's milk<br>Standard Starter and follow up formula without added HMOs or MOS containing lower levels of myelin nutrients | Other: Control Formula<br>* Cow's milk-based infant formula with standard nutritional composition<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Scores on the Cognitive subscale of the Bayley Scale of Infant Development, 4th Edition | Change in the scores on the Cognitive subscale. The scores range from 40 to 160 and higher scores indicate a better cognitive outcome | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant sleep | Infant daytime and night-time sleep patterns, parent perception, and sleep-related behaviours will be assessed using the Brief Infant Sleep Questionnaire | 1.5-2 months, 6 months, 12 months, and 24 months | 
| Infant fecal microbiota | Overall fecal microbiota composition, diversity, microbiota community types will be assessed using next generation sequencing (NGS) technology | 1.5-2 months (but before starting study formula), and just prior to 6 months, and 12 months | 
| Infant immune and gut health biomarkers | Fecal markers of immune and gut barrier, such as but no restricted to total secretory IgA (sIgA), lipocalin-2, calprotectin, and α-1-antitrypsin will be assessed by ELISA | 1.5-2 months (but before starting study formula), 6 months, and 12 months | 
| Infant Global developmental status in all domains of the Bayley Scale of Infant Development, 4th Edition | Infant Language, motor, socio-emotional, adaptive behaviour, and cognitive scores will be assessed | 6 months, 9 months, 12 months, and 24 months | 
| Infant Visual attention | Developmental status of infants' visual attention will be assessed using the infant Gap-Overlap task | 4 months, 6 months, 9 months, and 12 months | 
| Infant Visual learning | Infant's quality of attention will be assessed using the infant visual habituation task as augmented with heart rate | 4 months, 6 months, 9 months, and 12 months | 
| Early language development | Assessed using the MacArthur-Bates Communicative Development Inventories | Words and Gestures (long form) at 12 months and Words and Sentences (long form) at 24 months | 
| Working memory and inhibitory control | Assessed using the A-not-B Invisible Displacement Task | 24 months | 
| Behavioral manifestations of executive function | Assessed using the Behavior Rating Inventory of Executive Function-Preschool version. The questionnaire consists of scales such as Inhibit, Shift, Emotional Control, working memory, plan and organize and Indexes such as Inhibitory Self control, Flexibility Index, Emergent metacognition index and Global Executive Composite. T scores are used to interpret the child's level of executive functioning on the BRIEF-P. scores provide information about a child's scores relative to the scores of children in the standardization sample | 24 months | 
| Infant temperament | Assessed using the Infant Behaviour Questionnaire Revised Short Form. The questionnaire assess dimensions of temperament along 14 scales on a 7-point Likert scale on behavior occurrence, with 1 being never and 7 being always (Activity level, Distress to limitations, Approach, Fear, Duration of orienting, smiling and laughter, vocal reactivity, Sadness, Perceptual sensitivity, High-intensity pleasure, Low-intensity pleasure, Cuddliness, Soothability, Falling Reactivity/Rate of Recovery From Distress) | 1.5-2 months, 6 months, and 12 months | 
| Child temperament | Child temperament will be assessed using the Early Childhood Behavior Questionnaire- Short Form. The questionnaire measures 18 discrete traits embedded within three higher-order factors on a 7-point Likert scale on behavior occurrence, with 1 being never and 7 being always. Negative Affect (Discomfort, Fear, Frustration, Motor Activation, Sadness, Perceptual Sensitivity, Shyness, Soothability), Surgency (Impulsivity, Activity Level, High Intensity Pleasure, Sociability, Positive Anticipation), and Effortful Control (Inhibitory Control, Attention Shifting, Low Intensity Pleasure, Cuddliness, and Attentional Focusing). | 24 months |