Background
Probiotics
Prebiotics
L-glutamine
Methods
Study design and study setting
Study population
Inclusion criteria | |
1) Gestational age of 24 + 0 to < 30 + 0 weeks | |
2) Less than 72 h old and the intention to receive the first administration of study product between 48 and 72 h after birth | |
3) Written informed consent from custodial parent(s) | |
Exclusion criteria | |
1) Any relevant proven or suspected chromosomal anomaly, metabolic disorder, genetic syndrome or congenital central nervous system malformation | |
2) Presence of any gastrointestinal malformation | |
3) No realistic prospect of survival (e.g. severe brain injury), at the discretion of the attending physician | |
4) Concomitant participation in other intervention studies (for example, but not exclusively, those studies involving investigational or marketed nutritional or pharmaceutical products) that could impact on the main outcome parameters and/or infant safety | |
5) Expected or foreseen inability of the infant and/or their families to adhere to protocol instructions | |
6) Admission from an extra regional hospital, unless that hospital is a study site | |
7) Current use of gastric acid inhibitors: H2-receptor antagonists (including ranitidine) or proton pump inhibitors (including omeprazole) |
Treatment allocation and blinding
Study products
Supplementation
Outcome measures
Primary outcome
Secondary outcomes
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White matter injury, measured with the white matter injury score according to Kidokoro et al., [57] which evaluates cystic lesions, focal signal abnormality, myelination delay, thinning of the corpus callosum, dilated lateral ventricles and volume reduction on T2- and T1-weighted MR images acquired at TEA.
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Brain tissue volumes (cerebellum, cortical grey matter, unmyelinated white matter, deep nuclear grey matter, ventricular volumes and extracerebral cerebrospinal fluid) and cortical morphology (sulcation index, cortical surface area and cortical thickness) assessed using the segmentation method of Moeskops et al. [58] of T2- and T1-weighted MR images made at TEA.
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The occurrence of serious neonatal infections (defined as culture proven or clinical sepsis with associated clinical symptoms; clinically significant NEC [i.e., Bell’s stage two or higher]; meningitis with or without positive culture; or pneumonia [positive culture of tracheal aspirate, bronchial secretion, or sputum positive for microorganisms with associated clinical symptoms]) [45, 51] until TEA.
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Serum concentrations of specific circulating inflammatory markers such as IL-6, IL-10, TNF-α and IL-8/CXCL8 measured with flow cytometry and Luminex at 7, 21 and 42 days postnatal, 30 and 36 weeks postmenstrual age, discharge to other hospital and TEA (optional, in a subgroup).
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Motor and cognitive development assessed with the Bayley Scales of Infant and Toddler Development, Third Edition, [59] at 24 months corrected age.
Safety outcomes
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Occurrence, type and duration of (Serious) Adverse Events.
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Adequate growth for weight (g/kg/week), length (cm/week) and head circumference (cm/week) until the end of intervention.
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Growth velocity and anthropometric z-scores until 24 months corrected age.
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Number of days of parenteral nutrition.
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Time in days to achieve full enteral nutrition (defined as 120 ml/kg/day for 1 day).
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Feeding tolerance (frequency and daily volume of gastric residuals, the occurrence of diarrhoea and constipation and stool frequency).
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Serum glutamine and glutamate concentrations (optional, in a subgroup).