An interventional study of Bovine Colostrum (BC) / intervention group and FM85 / control group in Growth, Necrotizing Enterocolitis and Late-Onset Sepsis, sponsored by Per Torp Sangild. Completed at 7 sites in Denmark. Open to participants aged 5 Days to 3 Weeks. Per ClinicalTrials.gov, last updated 2022-03-23.
Sponsored by Per Torp Sangild · Not applicable, Interventional, and Supportive care
Very preterm infants (\<32 weeks gestation) with very low birth weight (VLBW, \<1500 g) show immaturity of organs and have high nutrient requirements forgrowth and development. In the first weeks, they have difficulties tolerating enteral nutrition (EN) and are often given supplemental parenteral nutrition (PN). A fast transition to full EN is important to improve gut maturation and reduce the high risk of late-onset sepsis (LOS), related to their immature immunity in gut and blood. Conversely, too fast increase of EN predisposes to feeding intolerance and necrotizing enterocolitis (NEC). Further, human milk feeding is not sufficient to support nutrient requirements for growth of VLBW infants. Thus, it remains a difficult task to optimize EN transition, achieve adequate nutrient intake and growth, and minimize NEC and LOS in the postnatal period of VLBW infants.
Mother´s own milk (MM) is considered the best source of EN for VLBW infants and pasteurized human donor milk (DM) is the second choice, if MM is absent or not sufficient. The recommended protein intake is 4-4.5 g/kg/d for VLBW infants, when the target is a postnatal growth similar to intrauterine growth rates. This amount of protein cannot be met by feeding only MM or DM. Thus, it is common practice to enrich human milk with human milk fortifiers (HMFs, based on ingredients used in infant formulas) to increase growth, bone mineralization and neurodevelopment, starting from 7-14 d after birth and 80-160 ml/kg feeding volume per day. Bovine colostrum (BC) is the first milk from cows after parturition and is rich in protein (80-150 g/L) and bioactive components. These components may improve gut maturation, NEC protection and nutrient assimilation, even across species. Studies in preterm pigs show that feeding BC alone, or DM fortified with BC, improves growth, gut maturation and NEC resistance during the first 1-2 weeks, relative to DM, or DM fortified with conventional HMFs.On this background, we hypothesize that BC, used as a fortifier for MM or DM, can induce similar growth and better NEC and LOS resistance, than conventional fortifiers. A pilot trial is required 1) to test the feasibility and initial safety of BC as a fortifier (e.g. similar growth rates and clinical variables as conventional fortification), 2) to calculate the sample size for a later, larger RCT with NEC +LOS as the primary outcome, and 3) record paraclinical outcomes associated with type of fortifier.
The main objectives of this multicentre, non-blinded, pilot, RCT are:
Participants Parents to eligible very preterm infants admitted to the Neonatal Intensive Care Units (NICU) at Nanshan People's Hospital (NAN) and Baoan Maternal and Children's Hospital in Shenzen, China will be asked for participation.
Since this is a pilot trial, a conventional sample size calculation, using only one primary outcome, is not required. The aim is to include 200 infants (100 per group), which is expected to give sufficient strength to demonstrate effects on the chosen feasibility outcomes and secondary blood and stool variables (see protocol). Statistical analyses will be performed blindly on both intention-to-treat and per protocol basis. Continuous outcomes will be summarized as mean and standard deviation (e.g., body weight) or median and interquartile range (e.g. time to reach full enteral feeding). Binary outcomes (e.g. incidence of NEC) will be presented as counts and percentages. To test the preliminary effects of BC, clinical and para-clinical outcomes will be compared between the two groups. The estimates will be presented as relative risk and absolute risk difference, difference between means, or hazard ratio, depending on the type of outcome. The estimates will be presented with a 95% confidence interval. Further statistical analyses are described in the protocol.
216 studies on the registry are indexed under Enterocolitis; 26 are open to participants now.
This study's enrollment of 252 is above the median of 100 across 123 interventional studies indexed under Enterocolitis.
Browse Enterocolitis studies →Per Torp Sangild is the lead sponsor of 5 studies on the registry; none are open to participants now.
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Exclusion criteria:
Preterm infants are supplemented with bovine colostrum (BC) as a fortifier to human milk. BC is the first milk from cows after parturition and is a rich source of protein (80-150 g/L) and bioactive components, including lactoferrin, lysozyme, lactoperoxidase, immunoglobulins, and growth factors. The product is supplied in a sterile, powdered form and consists of unmodified, intact BC.
Dietary Supplement: Bovine Colostrum (BC) / intervention group
Preterm infants are supplemented with PreNAN FM85 as fortifier to human milk. PreNAN FM85 contains partially hydrolyzed protein and maltodextrin including vitamins and minerals. The product is supplied in a powdered form.
Dietary Supplement: FM85 / control group
Infants randomized to the intervention group will receive a maximum of 2.8 g bovine colostrum (BC, Biofiber, Gesten, Denmark), as the HMF added to 100 ml of MM and/or DM, when EN has reached a dose of 100-140 ml/kg/d and blood urea nitrogen (BUN) levels are below 5 mmol/l. The infants starts with 1 g (0.5 g protein) BC per 100 ml human milk on the first day, increased to 2 g (1.0 g protein) on day 3, and finally 2.8 g (1.4 g protein) on day 5, if the infants only receive DM. The intervention begins if the infants meet the inclusions criteria and the intervention lasts until the infants reach post menstrual age (PMA) 34+6 weeks or are discharged home (including participating in an "early discharge program"), or are transferred to non-participating neonatal units, whichever comes first.
Infants randomized to the control group will receive a maximum of 4 g PreNAN FM85 (Nestlé, Vevey, Switzerland) as HMF, added to 100 ml MM and/or DM, when EN has reached a dose of 100-140 ml/kg/d and BUN levels are below 5 mmol/l. The infants starts with 1 g (0.35 g protein) FM85 per 100 ml human milk on the first day, which will be increased to 3 g (1.05 g protein) on day 3 and finally 4 g (1.4 g protein) on day 5, if the infants only receive DM. FM85 is the standard HMF used in all participating hospitals in Denmark. The infants will receive FM85 as the HMF as long as additional protein in the milk is needed.
Body weight
Weight gain in grams from birth to discharge from hospital. Weight at different time points will be calculated into z-scores according to a reference. Delta z-scores will be used to evaluate growth and for comparison between groups.
Time frame: From start of intervention to hospital discharge, or up to 14 weeks
Incidence of necrotizing entercolitis (NEC)
Number of infants in each group diagnosed with necrotizing enterocolitis (NEC) defined as Bell's stage II or above (Kliegman \& Walsh 1987).
Time frame: From start of intervention to hospital discharge, or up to 14 weeks
Incidence of late-onset sepsis (LOS)
Number of infants in each group diagnosed with late-onset sepsis defined as clinical signs of infection \>2 days after birth with antibiotic treatment for ≥5 days (or shorter than 5 days if the participant died) with or without one positive bacterial culture in blood or cerebral spinal fluid (CSF).
Time frame: From start of intervention to hospital discharge, or up to 14 weeks
Feeding intolerence
Proportion of days with a feeding volume less than 50% of the total planned volume per day
Time frame: From start of intervention to end of study period at post menstrual age 34+6 weeks, or up to 8 weeks
Time to reach full enteral feeding
Number of days to full enteral feeding is reached - defined as the time when \>150 ml/kg/d is reached and parenteral nutrition has been discontinued
Time frame: From birth to full enteral feeding, or up to 8 weeks
Days on parenteral nutrition
Number of days that the infant receives intravenous intakes of protein and/or lipid and/or glucose.
Time frame: From birth to end of intervention, or up to 8 weeks
Length of hospital stay
Number of days in hospital, defined as days from birth until final discharge (including the days covered by an early discharge programme).
Time frame: From birth until until final discharge, or up to 14 weeks
Blood urea nitrogen (BUN)
Blood urea nitrogen concentration is measured to evaluate the risk of excessive protein supply and immature kidney function
Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
Blood minerals
Blood levels of ionized phosphate, calcium and zink are measured to evaluate the risk of inadequate or excessive dietary mineral supply
Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
Blood haemoglobin
Determined to evaluate risk of anaemia and inadequate iron supply
Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
Body length
Recorded as a measure of growth in cm by standardized measuring procedures
Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
Head circumference
Recorded as a measure of head growth in cm by standardized measuring procedures
Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
Plasma amino acid levels
To determine whether individual amino acids are within their normal range. Specific attention is given to amino acids used as markers for excessive protein supply (tyrosine) and gut function (citrulline, arginine)
Time frame: Prior to and after 1 and 2 weeks of intervention
Plasma intestinal fatty acid binding protein (i-FABP)
Determine the concentration, as a marker of gut epithelial integrity
Time frame: Prior to and after 1 and 2 weeks of intervention
Plasma neutrophil extracellular trap (NET) components
Determine the concentration, as a marker systemic inflammation
Time frame: Prior to and after 1 and 2 weeks of intervention
Plasma lactoferrin
Determine the concentration, as a marker systemic inflammation
Time frame: Prior to and after 1 and 2 weeks of intervention
Plasma interleukin (IL) 8
Determine the concentration, as a marker systemic inflammation
Time frame: Prior to and after 1 and 2 weeks of intervention
Fecal microbiota
Determine the 16S microbiome density and diversity, as a marker for gut microbiota stability
Time frame: Prior to and after 1 and 2 weeks of intervention
Fecal interleukin (IL) 8
Determine concentration per g feces, as marker of gut inflammation
Time frame: Prior to and after 1 and 2 weeks of intervention
Fecal calprotectin (S100-A8/9)
Determine concentration per g faeces, as marker of gut inflammation
Time frame: Prior to and after 1 and 2 weeks of intervention
Fecal metabolites (short-chain fatty acids, SCFAs)
Determine concentration per g faeces, including acetate, butyrate and propionate levels, as markers of bacterial nutrient fermentation
Time frame: Prior to and after 1 and 2 weeks of intervention
Feasibility of study design
Record parental consent rates, infant recruitment rates, proportion of incomplete datasets
Time frame: From study initiation to study completion at each participating hospital, data collected from each unit by the end of the study
Feasibility of diet intervention
Determine by semi-quantitative questionaire evaluation, if the investigated BC product, relative to the control product, increases/decreases the work load or complications experienced by the involved clinical staff (doctors, nurses)
Time frame: From study initiation to study completion at each participating hospital, data collected from each unit by the end of the study
Plan to share: Undecided
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Per Torp Sangild