Clinical trial NCT03537365: Bovine Colostrum as a Fortifier Added to Human Milk for Preterm Infants
Official title: Bovine Colostrum to Fortify Human Milk for Preterm Infants A Randomized, Controlled Pilot Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Growth
Necrotizing Enterocolitis
Late-Onset Sepsis
Feeding Intolerance
Keywords: Human Milk Fortification
Bovine Colostrum
Very Preterm Infants
Enteral feeding
Human Milk
Neonatology
Colostrum
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Kolding Sygehus
name: Herlev Hospital
name: Hvidovre University Hospital
name: Aarhus University Hospital
name: Odense University Hospital
name: North Zealand Hospital, Denmark
First posted: 2018-05-25
Enrollment: 252
Sex: ALL
Minimum age (years): 5
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A multicentre, non-blinded, pilot randomized controlled trial
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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

1. To investigate the safety, tolerability and the preliminary effects of BC, used as an HMF for MM and DM in very preterm infants.
2. To facilitate the determination of sample size for a later, larger RCT with NEC- and LOS-free survival as the primary outcome.
3. 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.

Eligibility criteria: Inclusion criteria:

1. 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)
2. DM is given at the unit when MM is absent (or insufficient in amount)
3. 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
4. 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:

1. Major congenital anomalies and birth defects
2. Infants who have had gastrointestinal surgery prior to randomization
3. Infants who have received infant formula prior to randomization

Primary outcomes:
measure: Body weight
timeFrame: From start of intervention to hospital discharge, or up to 14 weeks
measure: Incidence of necrotizing entercolitis (NEC)
timeFrame: From start of intervention to hospital discharge, or up to 14 weeks
measure: Incidence of late-onset sepsis (LOS)
timeFrame: From start of intervention to hospital discharge, or up to 14 weeks
Secondary outcomes:
measure: Feeding intolerence
timeFrame: From start of intervention to end of study period at post menstrual age 34+6 weeks, or up to 8 weeks
measure: Time to reach full enteral feeding
timeFrame: From birth to full enteral feeding, or up to 8 weeks
measure: Days on parenteral nutrition
timeFrame: From birth to end of intervention, or up to 8 weeks
measure: Length of hospital stay
timeFrame: From birth until until final discharge, or up to 14 weeks
measure: Blood urea nitrogen (BUN)
timeFrame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
measure: Blood minerals
timeFrame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
measure: Blood haemoglobin
timeFrame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
Other outcomes:
measure: Body length
timeFrame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
measure: Head circumference
timeFrame: Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks
measure: Plasma amino acid levels
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Plasma intestinal fatty acid binding protein (i-FABP)
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Plasma neutrophil extracellular trap (NET) components
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Plasma lactoferrin
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Plasma interleukin (IL) 8
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Fecal microbiota
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Fecal interleukin (IL) 8
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Fecal calprotectin (S100-A8/9)
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Fecal metabolites (short-chain fatty acids, SCFAs)
timeFrame: Prior to and after 1 and 2 weeks of intervention
measure: Feasibility of study design
timeFrame: From study initiation to study completion at each participating hospital, data collected from each unit by the end of the study
measure: Feasibility of diet intervention
timeFrame: From study initiation to study completion at each participating hospital, data collected from each unit by the end of the study
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet (RH)
city: Herlev
country: Denmark
facility: Herlev Hospital
city: Hillerød
country: Denmark
facility: North Zealand Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital (HH)
city: Kolding
country: Denmark
facility: Kolding Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
Study officials:
affiliation: Odense University Hospital
name: Gitte Zachariassen, MD., PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: Per Sangild, Prof
role: STUDY_CHAIR
References:
citation: Ahnfeldt AM, Hyldig N, Li Y, Kappel SS, Aunsholdt L, Sangild PT, Zachariassen G. FortiColos - a multicentre study using bovine colostrum as a fortifier to human milk in very preterm infants: study protocol for a randomised controlled pilot trial. Trials. 2019 May 22;20(1):279. doi: 10.1186/s13063-019-3367-7.