Bovine Colostrum as a Human Milk Fortifier for Preterm Infants (FortiColos-Ⅱ)

• ClinicalTrials.gov Identifier: NCT03822104
• Recruitment Status: Completed
• First Posted: January 30, 2019
• Last Update Posted: January 28, 2022
• Sponsor: Per Torp Sangild
• Information provided by (Responsible Party): Per Torp Sangild, Rigshospitalet, Denmark

Study Description

Brief Summary:

Very preterm infants (<32 weeks gestation) show the immaturity of organs and have high nutrient requirements for growth 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 very preterm 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 very preterm infants. Mother´s own milk (MM) is considered the best source of EN for very preterm 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 very low birth 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, the investigators hypothesize that BC, used as a fortifier for MM or DM, can reduce feeding intolerance than conventional fortifiers.

Condition or disease	Intervention/treatment	Phase
Feeding Intolerance; Necrotizing Enterocolitis; Postnatal Growth; Late-Onset Neonatal Sepsis	Dietary Supplement: Bovine Colostrum; Dietary Supplement: FM85	Not Applicable

Detailed Description:

Objectives

1. To test if fortification of human milk with BC reduces feeding intolerance compared with currently used HMF.
2. To verify the safety and tolerability of BC fortification and to monitor the rates of growth, NEC and sepsis, as investigated in a parallel trial in Denmark

Trial design This study is a dual-center, non-blinded, two-armed, randomized, controlled trial.

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 Shenzhen, China will be asked for participation.

Sample size 68 infants per group, 136 in total

Data type Clinical data

A parallel trial on BC used as human milk fortifier is conducting in Denmark (NCT03537365)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 139 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: Bovine Colostrum to Fortify Human Milk for Preterm Infants: A Randomized, Controlled Trial
• Actual Study Start Date: May 1, 2019
• Actual Primary Completion Date: June 13, 2021
• Actual Study Completion Date: July 8, 2021

Arms and Interventions

Arm	Intervention/treatment
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.	Dietary Supplement: Bovine Colostrum; 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 80-100 ml/kg/d. The infants start 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 lasts until the infants reach postmenstrual age (PMA) 35+6 weeks or in no-need of fortification due to sufficient growth, whichever comes first.
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.	Dietary Supplement: FM85; 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 80-100 ml/kg/d. 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. The infants will receive FM85 as the HMF as long as additional protein in the milk is needed until discharge.

Outcome Measures

Primary Outcome Measures :

1. Incidence of feeding intolerance [ Time Frame: From start of intervention until the infants reach PMA 35+6 weeks or are not in need of fortification due to sufficient growth, whichever comes first ]
   Number of infants in each group diagnosed with feeding intolerance for at least once. Feeding intolerance is defined as any pause of fortification or withhold of enteral feeding.

Secondary Outcome Measures :

1. Body weight [ Time Frame: Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks ]
   Weight gain in grams per kg body weight from birth to discharge. 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. Body length [ Time Frame: Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks ]
   Recorded as a measure of growth in cm by standardized measuring procedures
3. Head circumference [ Time Frame: Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks ]
   Recorded as a measure of head growth in cm by standardized measuring procedures
4. Incidence of necrotizing entercolitis (NEC) [ Time Frame: From the 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)
5. Incidence of late-onset sepsis (LOS) [ Time Frame: From the 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)
6. Time to reach full enteral feeding [ Time Frame: From birth to hospital discharge, or up to 14 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
7. Days on parenteral nutrition [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Number of days that the infant receives intravenous intakes of protein and/or lipid and/or glucose
8. Length of hospital stay [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Number of days in hospital, defined as days from birth until final discharge

Other Outcome Measures:

1. Volume of gastric residual [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Volume of aspirated gastric residuals in ml
2. Color of gastric residual [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   The color of aspirated gastric residuals categorized into 7 colours
3. Incidence of bloody gastric residual [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Number of infants in each group have had blood in the gastric residual
4. Frequency of stool per day [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Frequency of stool passed each day
5. Amount of the stool [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]

   Using a 4-level pre-defined scale Amount of stool on the diaper: the percentage of area covered by stool on the diaper.

   • 1 smear;
   • 2 up to 25%;
   • 3 25-50%;
   • 4 >50%
6. Color of the stool [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   The color of stools categorized into 6 colors
7. Consistency of the stool [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Using a 4-level pre-defined scale
8. Total daily volume of enteral nutrition (EN) and parenteral nutrition (PN) [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Volume of EN (including MM, DM, infant formula, and fortification) and PN in take
9. Levels of macronutrients intake from EN and PN [ Time Frame: From birth to hospital discharge, or up to 14 weeks ]
   Calculated based on the volume and composition of EN and PN

Eligibility Criteria

• Ages Eligible for Study: up to 3 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Very preterm infants born between gestational age 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. Signed parental consent

Exclusion Criteria:

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

Contacts and Locations

Locations

China, Guangdong

Shenzheng Baoan Maternity and Child Healthcare Hospital (SBMCH)

Shenzhen, Guangdong, China, 518133

China

Shenzhen Nanshan People's Hospital

Shenzhen, China

Sponsors and Collaborators

Per Torp Sangild

Investigators

• Study Chair: Per T Sangild; Rigshospitalet, Denmark
• Principal Investigator: Ping Zhou; Shenzheng Baoan Maternity and Child Healthcare Hospital

More Information

• Responsible Party: Per Torp Sangild, Professor, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT03822104
• Other Study ID Numbers: FortiColos-CN
• First Posted: January 30, 2019
• Last Update Posted: January 28, 2022
• Last Verified: January 2022

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

Keywords provided by Per Torp Sangild, Rigshospitalet, Denmark:

Very Preterm Infants; Human Milk Fortifier; Bovine Colostrum; Enteral Feeding; Nutrition; Human milk

Additional relevant MeSH terms:

Neonatal Sepsis; Enterocolitis; Enterocolitis, Necrotizing; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Sepsis; Infections; Infant, Newborn, Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes