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Completed

NCT Number: NCT03537365

Bovine Colostrum as a Fortifier Added to Human Milk for Preterm Infants

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.

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Key information

Conditions

Growth Digestive System Diseases Enterocolitis Enterocolitis, Necrotizing Feeding Intolerance Gastroenteritis Gastrointestinal Diseases Intestinal Diseases Late-onset Sepsis Necrotizing Enterocolitis

Age range

5 day–3 week

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Aarhus University Hospital, Aarhus, Denmark

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About this study

The main objectives of this multicentre, non-blinded, pilot, RCT are:

  • To investigate the safety, tolerability and the preliminary effects of BC, used as an HMF for MM and DM in very preterm infants.
  • To facilitate the determination of sample size for a later, larger RCT with NEC- and LOS-free survival as the primary outcome.
  • To assess the feasibility of study procedures, incl. recruitment rates, parental consent, adherence, sample collection, and clinical routines.

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Very preterm infants born between GA 26+0 and 30+6 weeks (from the first day of the mother's last menstrual period and/or based on fetal ultrasound)
  • DM is given at the unit when MM is absent (or insufficient in amount)
  • Infants judged by the attending physician to be in need of nutrient fortification, as added in the form of HMF to MM and/or DM
  • Infants admitted and staying at participating units at least until post menstrual age (PMA, gestational age + weeks and/or days since birth) 34+6 weeks, before being transferred to non-participating units, or going home participating in an "early discharge program". The infants can be transferred from one participating unit to another participating unit.

Exclusion criteria

  • Major congenital anomalies and birth defects
  • Infants who have had gastrointestinal surgery prior to randomization
  • Infants who have received infant formula prior to randomization

Treatment and study plan

Bovine Colostrum (BC) / intervention group

Dietary Supplement

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.

FM85 / control group

Dietary Supplement

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.

Primary outcomes

  1. Body weight

    Time frame: From start of intervention to hospital discharge, or up to 14 weeks

    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.

  2. Incidence of necrotizing entercolitis (NEC)

    Time frame: From start of intervention to hospital discharge, or up to 14 weeks

    Number of infants in each group diagnosed with necrotizing enterocolitis (NEC) defined as Bell's stage II or above (Kliegman & Walsh 1987).

  3. Incidence of late-onset sepsis (LOS)

    Time frame: From start of intervention to hospital discharge, or up to 14 weeks

    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).

Secondary outcomes

  1. Feeding intolerence

    Time frame: From start of intervention to end of study period at post menstrual age 34+6 weeks, or up to 8 weeks

    Proportion of days with a feeding volume less than 50% of the total planned volume per day

  2. Time to reach full enteral feeding

    Time frame: From birth to full enteral feeding, or up to 8 weeks

    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

  3. Days on parenteral nutrition

    Time frame: From birth to end of intervention, or up to 8 weeks

    Number of days that the infant receives intravenous intakes of protein and/or lipid and/or glucose.

  4. Length of hospital stay

    Time frame: From birth until until final discharge, or up to 14 weeks

    Number of days in hospital, defined as days from birth until final discharge (including the days covered by an early discharge programme).

  5. Blood urea nitrogen (BUN)

    Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

    Blood urea nitrogen concentration is measured to evaluate the risk of excessive protein supply and immature kidney function

  6. Blood minerals

    Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

    Blood levels of ionized phosphate, calcium and zink are measured to evaluate the risk of inadequate or excessive dietary mineral supply

  7. Blood haemoglobin

    Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

    Determined to evaluate risk of anaemia and inadequate iron supply

Other outcomes

  1. Body length

    Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

    Recorded as a measure of growth in cm by standardized measuring procedures

  2. Head circumference

    Time frame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

    Recorded as a measure of head growth in cm by standardized measuring procedures

  3. Plasma amino acid levels

    Time frame: Prior to and after 1 and 2 weeks of intervention

    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)

  4. Plasma intestinal fatty acid binding protein (i-FABP)

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine the concentration, as a marker of gut epithelial integrity

  5. Plasma neutrophil extracellular trap (NET) components

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine the concentration, as a marker systemic inflammation

  6. Plasma lactoferrin

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine the concentration, as a marker systemic inflammation

  7. Plasma interleukin (IL) 8

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine the concentration, as a marker systemic inflammation

  8. Fecal microbiota

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine the 16S microbiome density and diversity, as a marker for gut microbiota stability

  9. Fecal interleukin (IL) 8

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine concentration per g feces, as marker of gut inflammation

  10. Fecal calprotectin (S100-A8/9)

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine concentration per g faeces, as marker of gut inflammation

  11. Fecal metabolites (short-chain fatty acids, SCFAs)

    Time frame: Prior to and after 1 and 2 weeks of intervention

    Determine concentration per g faeces, including acetate, butyrate and propionate levels, as markers of bacterial nutrient fermentation

  12. Feasibility of study design

    Time frame: From study initiation to study completion at each participating hospital, data collected from each unit by the end of the study

    Record parental consent rates, infant recruitment rates, proportion of incomplete datasets

  13. Feasibility of diet intervention

    Time frame: From study initiation to study completion at each participating hospital, data collected from each unit by the end of the study

    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)

Sponsors and collaborators

Lead sponsor

Per Torp Sangild

Other

Collaborators

  • Aarhus University Hospital
  • Herlev Hospital
  • Hvidovre University Hospital
  • Kolding Sygehus
  • Nordsjaellands Hospital
  • Odense University Hospital

Registry information

Official study title

Bovine Colostrum to Fortify Human Milk for Preterm Infants A Randomized, Controlled Pilot Trial

Acronym: FortiColos

Important dates

Study start
2017
Primary completion
2022
Study completion
2022
First posted
May 25, 2018
Registry last updated
Mar 23, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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