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

• ClinicalTrials.gov Identifier: NCT03537365
• Recruitment Status: Recruiting
• First Posted: May 25, 2018
• Last Update Posted: January 22, 2019
• Sponsor: Per Torp Sangild
• Collaborators: Kolding Sygehus; Herlev Hospital; Hvidovre University Hospital; Aarhus University Hospital; Odense University Hospital; North Zealand Hospital, Denmark
• Information provided by (Responsible Party): Per Torp Sangild, Rigshospitalet, Denmark

Tracking Information

• First Submitted Date: January 16, 2018
• First Posted Date: May 25, 2018
• Last Update Posted Date: January 22, 2019
• Actual Study Start Date: December 4, 2017
• Estimated Primary Completion Date: December 1, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2018)

• 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.
• 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).
• 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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 24, 2018)

• 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
• 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
• 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.
• 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).
• 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
• 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
• 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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: May 24, 2018)

• 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
• 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
• 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)
• 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
• 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
• Plasma lactoferrin [ Time Frame: Prior to and after 1 and 2 weeks of intervention ]
  Determine the concentration, as a marker systemic inflammation
• Plasma interleukin (IL) 8 [ Time Frame: Prior to and after 1 and 2 weeks of intervention ]
  Determine the concentration, as a marker systemic inflammation
• 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
• 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
• 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
• 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
• 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
• 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)

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A multicentre, non-blinded, pilot randomized controlled trial

Masking: Single (Outcomes Assessor)
Primary Purpose: Supportive Care

Condition

• Growth
• Necrotizing Enterocolitis
• Late-Onset Sepsis
• Feeding Intolerance

Intervention

• Dietary Supplement: Bovine Colostrum (BC) / intervention 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.

• Dietary Supplement: FM85 / control group

  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.

Study Arms

• Experimental: Bovine Colostrum / intervention group
  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.
  Intervention: Dietary Supplement: Bovine Colostrum (BC) / intervention group
• Active Comparator: FM85 / control 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.
  Intervention: Dietary Supplement: FM85 / control group

• Publications *: 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 24, 2018): 200
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 1, 2022
• Estimated Primary Completion Date: December 1, 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 3 Weeks (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Gitte Zachariassen, MD., PhD; +45 21 36 04 26; Gitte.Zachariassen@rsyd.dk

Contact: Agnethe Ahnfeldt, MD.; +45 35 32 81 59; agnethe.ahnfeldt@sund.ku.dk

• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT03537365
• Other Study ID Numbers: FortiColos (pilot RCT)
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Per Torp Sangild, Rigshospitalet, Denmark
• Study Sponsor: Per Torp Sangild

Collaborators

• Kolding Sygehus
• Herlev Hospital
• Hvidovre University Hospital
• Aarhus University Hospital
• Odense University Hospital
• North Zealand Hospital, Denmark

Investigators

• Principal Investigator: Gitte Zachariassen, MD., PhD; Odense University Hospital
• Study Chair: Per Sangild, Prof; Rigshospitalet, Denmark

• PRS Account: Rigshospitalet, Denmark
• Verification Date: October 2018