Use of a Liquid Supplement Containing 2 Human Milk Oligosaccharides (HMOs) in Preterm Infants

Study Overview
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Brief Summary
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This is a prospective, randomized, double-blind, placebo-controlled trial in preterm infants conducted at least 4 centers in France, consisting of 2 parallel groups. The experimental group will receive a neonatal supplement containing 2 specific HMOs. The control group will receive a placebo neonatal supplement that does not contain any HMOs, but matched to the experimental product in energy content. This study will include a total of approximately 86 male and female preterm infants born between 27 and 32 weeks' gestational age with birth weight ≤1700 g, who are younger than 7 days of age. The primary objective of the study is to demonstrate the safety and tolerance of HMOs in preterm infants by monitoring weight gain rates in both of the two randomized groups.

Official Title
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Use of a Liquid Supplement Containing 2 Human Milk Oligosaccharides (HMOs) in Preterm Infants: a Double-blind, Randomized, Controlled Trial

Conditions
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Premature Infant

Intervention / Treatment
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* Dietary Supplement: HMO supplement
* Dietary Supplement: Placebo comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infant's birth weight ≤1700 g. Infant's gestational age ≥ 27 weeks + 0 days and ≤ 32 weeks + 6 days. Infant is clinically stable Infants are eligible to start HMOs / placebo as soon as possible after birth, but still within the first 7 days of life. Written informed consent has been obtained from the parents/legally acceptable representative (LAR). Exclusion Criteria: Parents not willing / not able to comply with the requirements of study protocol. Infants receiving ongoing prophylactic antifungal therapies. Infants experiencing early onset sepsis. Major congenital or chromosomal abnormality known to affect growth. Liver failure. Severe intrauterine growth restriction (IUGR) as defined by having birth weight less than 2nd percentile on the Fenton growth chart. Peri-/intra-ventricular haemorrhage (grade 3-4 in Papille classification) . Infant in critical condition needing intubation or inotropic agents for treatment. Infant requiring prolonged (more than 3 doses) of steroid treatment. Infants' participation in another interventional clinical trial that would have significant impact on current study's results. Infants who have already achieved Full Enteral Feeding (FEF) prior to enrolment, using the definition accepted by neonatal unit as per standard practice (150 mL/kg/day).

Ages Eligible for Study
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Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Formula<br>The experimental group will receive a liquid supplement containing 2 specific HMOs | Dietary Supplement: HMO supplement<br>* HMO supplement will be given three times a day, not mixed with any feeding.<br>|
| Placebo Comparator: Control Formula<br>The control group will receive a liquid placebo | Dietary Supplement: Placebo comparator<br>* Control product without any HMOs. The Placebo Comparator will be matched to the experimental product in energy content.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feeding tolerance | The primary objective is to demonstrate non-inferiority in feeding tolerance (defined as number of days to reach full enteral feeding) of preterm infants receiving a liquid supplement composed of 2 HMOs compared to those receiving the placebo. | Change from Full Enteral Feeding (FEF) Day 1 (start of FEF defined as achieving 150ml/day/kg of enteral feeding and discontinuation of parenteral feeding) and FEF Day 21 (approximately 5 weeks after enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length | Through standardized measurement for neonates | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Head circumference | Through standardized measurement for neonates | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Weight gain | Through standardized measurement for neonates | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Assessment of infant illnesses and infections | Through Adverse Event reporting | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Tolerance to feeding regimen | Through neonatal unit records | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Physical signs of gastrointestinal tolerance | Through neonatal unit records | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Breast milk composition such as energy, carbohydrate, proteins and fats using mid-infrared transmission methods | Macro and micro nutrients | Change from enrolment (baseline) (if feasible) until FEF Day 21, average of 5 weeks | 
| Standard Adverse Event reporting for safety assessment | Through investigator-confirmed Adverse Event reporting | Change from enrolment (baseline) (if feasible) through study completion, average of 4 months | 
| Fecal microbiota composition and diversity | Fecal microbiota composition and diversity will be assessed using next generation shotgun metagenomics sequencing to provide taxonomic composition and diversity metrics. Quantifiable changes from baseline and between feeding groups in absolute concentrations of bifidobacteria will be assessed using quantifiable polymerase chain reaction | Change from enrolment (baseline) through two-months corrected age visit | 
| Fecal metabolic profile | Measures of fecal metabolism will include fecal power of hydrogen (pH) and fecal organic acids (including lactate, propionate, butyrate, acetate, isobutyrate, isovalerate, valerate, formic acid, hexanoic acid, caprylic acid, capric acid, pelargonic acid, undecanoic acid, dodecanoic acid and total fecal organic acids). | Change from enrolment (baseline) through two-months corrected age visit | 
| Markers for gut health, gut maturation and immune status | Markers for gut health, gut maturation and immune status will be assessed through measures of: Fecal level of calprotectin, alpha 1 antitrypsin, pancreatic elastase, human beta-defensin 2 , secretory immunoglobulin A, Plasma level of citrulline and twenty four additional Amino Acids Urinary levels of intestinal fatty acid binding protein | Change from enrolment (baseline) (if feasible) until FEF Day 21 | 
| Early life development outcomes | Aligned with standard routine care, post-discharge clinical assessments of preterm infants include clinically relevant events since last visit, feeding practice (complementary feeding, adequate food intake), Gastrointestinal-related symptoms (sleep, crying), somatic examination (physical examination of skin, digestion, abdomen, hip), Neurosensory Examination (hearing / visual function, gross motor), Relationship and Communication Development (normal or abnormal communication, neurological or psychomotor examination, relationship / behavior disorders). All clinical assessments will be standardized across sites. Ages and Stages Questionnaire-3 will be administered to parents to assess their report of child's developmental progress based on Communication, Gross Motor, Fine Motor, Problem Solving, and Personal-Social domains. | At 12 Months Corrected age Visit, 18 Months Corrected age Visit, and 24 Months Corrected age Visit | 
| Cognitive development outcomes | Will be assessed through the composite scores or scale scores of the Bayley Scales of Infant and Toddler Development - Third Edition (Bayley-III) | 24 Months Corrected age Visit |