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Bovine Colostrum for Preterm Newborns (PreColos-RCT)

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ClinicalTrials.gov Identifier: NCT03085277
Recruitment Status : Active, not recruiting
First Posted : March 21, 2017
Last Update Posted : March 17, 2021
Sponsor:
Collaborators:
Sixth Affiliated Hospital, Sun Yat-sen University
Maternal and Child Health Hospital of Foshan
Shenzhen People's Hospital
Shenzhen Luohu Maternal and Child Health Hospital
Guangming District People's Hospital of Shenzhen
Longgang District Central Hospital of Shenzhen
Shenzhen Nanshan Maternity and Child Healthcare Hospital
Zhuhai Maternal and Child Health Care Hospital
Dongguan Women and Children's Hospital
Information provided by (Responsible Party):
Per Torp Sangild, Rigshospitalet, Denmark

Tracking Information
First Submitted Date  ICMJE March 14, 2017
First Posted Date  ICMJE March 21, 2017
Last Update Posted Date March 17, 2021
Actual Study Start Date  ICMJE July 1, 2017
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 11, 2020)
Time to full enteral feeding [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
Full feeding volume is defined as the first day a participant receives 120 ml/kg/d for a consecutive period of 72 hours.
Original Primary Outcome Measures  ICMJE
 (submitted: March 14, 2017)
Time to full enteral feeding [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
Full feeding volume is defined as the first day a participant receives 150 ml/kg/d for a consecutive period of 72 hours.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2017)
  • Combined incidence of severe neonatal infections (NEC, LOS, Meningitis) and mortality [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    LOS: defined as one positive bacterial culture in blood occurring > 3 days after birth with clinical signs of infection and with antibiotics treatment for ≥ 5 days. Clinical sepsis: Negative bacterial culture in blood, but the infants have clinical signs of infection and fulfil more than 2 of the following criteria: (1) Decrease in WBC , or increase in WBC(2) Immature//total neutrophils ≥0.16; (3) CRP ≥8 μg/mL; (4) Procalcitonin ≥ 2 ng/mL; (5) Platelets ≤ 100 ×109/ L. Meningitis: Positive bacterial culture from cerebrospinal fluid (CSF) with clinical signs. When negative, if the infants have clinical signs of meningitis and have the following changes in leucocyte counts or biochemistry values in CSF: 1) increase in leucocytes, 2) increase in total protein, and 3) increase in glucose, clinical meningitis should be recorded. NEC: Stage II or III according to modified Bell's criteria
  • The presence of feeding intolerance [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    Presence of feeding intolerance is defined as at any time when feeding is withheld by the neonatologists from day 1-7 and from day 8-14. The number of withheld meals of the prescribed feeding volume, and actually received volume from day 1-7 and from day 8-14, are recorded to indicate the degree of feeding intolerance.
  • Volume and color of gastric residual [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    The volume and color of gastric residuals withdrawn from the gastric tube are recorded by attending nurses, prior to a feeding
  • Days on PN [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    Days on PN are the total number of days that a participant receives any i.v. protein and/or lipid.
  • Days to regain birth weight [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    Days to regain birth weight is the total number of days that an infant used to regain his/her birth weight
  • Days of hospitalization [ Time Frame: From the start of intervention until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    Total number of days that a participant is hospitalized in the neonatal department for
  • Body weight, length, and head circumference [ Time Frame: Weekly until discharge home or reach a postconceptional age of 37 weeks, whichever comes first ]
    The weight, length, and head circumference of participants are measured every week
  • Routine blood tests [ Time Frame: On postnatal day 7 and 14 ]
    Blood tests (arteries blood) are performed according to the standard practices at each hospital, including blood gas, hematology, CRP, blood biochemistry for liver and kidney functions, bone health (e.g. phosphate and bone-specific alkaline phosphatase), mineral status (including sodium, potassium, calcium, magnesium, chloride, and phosphate), blood lipid profile, blood glucose, and immunoglobulin profile. The purpose is to monitor metabolic acidosis, infection, liver and kidney functions, bone health, and nutritional status in order to discover the possible safety risks or benefits of this BC intervention.
  • Plasma amino acid profile [ Time Frame: On postnatal day 7 and 14 ]
    Plasma amino acid profile is analyzed by mass spectrophotometry to investigate whether BC feeding provides a normal range of plasma amino acid pattern. Plasma citrulline concentration is considered as a biomarker for absorptive enterocyte mass and/or function.
  • Microbiota composition in feces [ Time Frame: On postnatal day 7 and 14 and at 1st and 2nd month. ]
    Fecal microbiota Is determined using high through-put sequencing technique to investigate whether the BC diet will affect the microbiota composition which is believed to be important for gut development and immunity, and to prevent overgrowth with pathogenic bacteria.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: January 21, 2019)
  • Levels of plasma markers [ Time Frame: On postnatal day 7 and 14 ]
    Levels of markers of the gut and systemic inflammation analyzed by untargeted and/or targeted proteomics or immune assays (e.g. NET-components, cell-free DNA, DNA-bound histone, lactoferrin, calprotectin, intestinal fatty acid binding protein) in relation to NEC and sepsis
  • Levels of whole blood markers [ Time Frame: On postnatal day 7, 14, and 28 ]
    Levels of markers of gut and systemic inflammation will be analyzed by transcriptomics and/or epigenetics using dried whole blood collected on filter papers, and related to NEC and sepsis
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bovine Colostrum for Preterm Newborns
Official Title  ICMJE Bovine Colostrum Versus Preterm Formula as the First Supplemental Nutrition for Very Preterm Infants, a Randomized, Controlled Trial
Brief Summary Feeding intolerance is a common problem in very preterm infants due to their immature digestive system. This intolerance extends the time to full enteral feeding and thereby also prolongs the time on parenteral nutrition (PN). Prolonged time to full enteral feeding may predispose these infants to a higher risk of growth retardation, infections and organ dysfunctions (e.g. liver, brain). Mother's own milk (MM) is considered the optimal nutrition for preterm infants and is superior to infant formula (including preterm formula, PF) in stimulating gut maturation, feeding tolerance, resistance against necrotizing enterocolitis (NEC) and late-onset sepsis (LOS), and long-term neurodevelopmental outcomes. However, MM is often absent, or not available in sufficient amounts, during the first days or weeks after preterm delivery. Human donor milk (DM) is probably a better supplement to MM than PF, but DM is not available for all hospitals. To supplement insufficient MM during the early neonatal period in hospital settings with no access to donor milk, we suggest that bovine colostrum (BC) may be used instead of PF for very preterm infants during early life. BC, the first milk from cows after birth, is a rich source of protein and bioactive components, including lactoferrin, lysozyme, lactoperoxidase, immunoglobulins, and various growth factors, such as IGF-I and -II, EGFs, and TGF-β. BC has repeatedly been shown to improve gut maturation and NEC/LOS resistance in a well-established piglet model of preterm infants. We suggest a randomized, controlled trial to investigate the effects of BC vs. PF, supplemented to MM during the first 2 weeks, on the time to full enteral feeding in very preterm infants.
Detailed Description

The Precolos-RCT is a multicenter, two-arm, unblinded, randomized, controlled trial. Infants are randomized to an intervention group which receives BC and a control group which receives PF. In detail, MM is always the first priority, when available. When MM is not available, or the available amounts do not fulfill the needs, infants in BC group will receive BC and control infants will receive PF, as the supplementary diets. Feeding should be initiated within 24-48 h after birth following a pre-defined nutritional guideline. BC intervention should not exceed postnatal day 14. After the intervention period, the participants in both groups will receive standard feeding which is the available MM with or without supplemental preterm infant formula. Infants will be followed until discharge home or reach a postconceptional age of 37 weeks, whichever comes first (discharge home/37 wks).

In general, parenteral and enteral nutrition should be given according to the following description:

Parenteral and enteral nutrition will be given according to the targeted daily fluid, energy, and protein levels suggested by ESPGHAN and CSPEN. Enteral nutrition should be given according to the feeding guideline and PN is used to ensure the targeted protein, energy, and lipid intake when enteral feeding is insufficient to provide fluid and nutrition. Participating hospitals should try their best to assist mothers in expressing their colostrum and milk and giving mother's colostrum as the first feeds. Enteral feeding should be given as soon as possible within 24h of life after randomization for infants with BW > 750g. For infants with BW ≤ 750 g, first feeding should be given within 24 h if mother's colostrum is available. Otherwise, first feeding should wait until day 2 for mothers to express their own colostrum. Mother's colostrum and MM is given as much as available, and when it is not available or in an insufficient amount, BC or PF is used during the intervention period to supplement the lacking volume. Infants should receive an initial feeding volume of 5-10 ml/kg/d and the volume should increase by 5-20 ml/kg/d until 150-160 ml/kg/d depending on their BW. The advancing rate of feeding should follow the suggested pace but also be adjusted according to the tolerability of the infants. If feeding intolerance occurs, feeding should be at a flat rate or be withheld according to predefined criteria in 'parenteral and enteral nutrition SOP'. If infants can tolerate more, feeding can be increased faster. Since total protein intake should be within 4-4.5 g/kg/d according to the ESPGHAN guideline25, the maximal daily volume of BC should be calculated based on the available volume of MM and protein levels in MM and BC. The protein supply from MM is calculated assuming a protein content of 1.5 g/100 mL27 (during the first 14 days) and the protein supply from colostrum is 8 g/100 mL (may adjust to changes according to the product specification of the batch in use when the difference is bigger than 5%). At the end of the intervention period, the enteral feeding in the intervention group will be gradually transferred to standard feeding (MM with supplemental PF when needed). Participants in the control group will keep receiving standard feeding after the intervention period. However, if a participant reaches term during their hospital stay, PF may be changed to term formulas according to local guidelines. The participating hospitals use four types of PF with similar nutrients composition and will remain the same throughout the study.

Although in the intervention group, infants should receive supplemental BC instead of PF during the intervention period, there is a possibility that PF and BC are simultaneously used as the supplemental diets. For example, when a participant in the intervention group can tolerate a higher EN volume than the available volume of MM plus the maximum daily volume of BC (due to max protein limitation), PF needs to be given to fulfill the total EN volume. Importantly, the volume of each milk diet will need to be adjusted according to the maximal protein intake of 4-4.5 g/kg/d. When BC intake has reached the maximal volume due to protein limitation but fluid requirement still needs to be fulfilled by PN, the PN should be given with an amino acid level of 0.5 g/kg/d (other nutrients are provided accordingly)and BC volume should be reduced by 6.25 ml/kg/d. A detailed guideline for parenteral and enteral nutrition is described in an SOP: 'Parenteral and enteral nutrition SOP'.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
When a preterm infant is delivered at these hospitals or transferred from other hospitals on the day of birth, responsible neonatologists/PIs/co-PIs will evaluate the infant for its eligibility. If the infant fulfills the recruitment criteria, parent(s) are informed and explained about the study and asked for permission to recruit their babies. After confirmed consent, the infant will be, per hospital, randomized to two groups in a 1:1 ratio. Infants should be recruited and randomized as soon as possible after birth and no later than 48 h. The first supplemental enteral feeding (PF or BC) can be given as soon as the infants are randomized. Randomization will be stratified by birth weight < 1000 g, birth weight ≥ 1000 g, and randomly permuted blocks of size 4 and 6 will be used. A random sequence list will be generated by computer software for each hospital and a corresponding sequence number can only be checked to see allocation after informed consent is given and the baby is enrolled.
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Enteral Feeding Intolerance
  • Necrotizing Enterocolitis
  • Late-Onset Neonatal Sepsis
Intervention  ICMJE
  • Dietary Supplement: Bovine Colostrum
    Bovine colostrum (BC) is the first milk from cows after birth and we suggest that BC may be used to supplement MM, instead of infant formula or DM. BC is a rich source of protein (up to 150 g/L) and bioactive components, including lactoferrin, lysozyme, lactoperoxidase, immunoglobulins, and various growth factors, such as, IGF-I and -II, EGFs, and TGF-β. BC has repeatedly been shown to have beneficial effects in a well-established piglet model of preterm infants, using various feeding regimens, including a gradual regimen that would mimic enteral feeding for preterm infants without access to MM during the first week.
  • Dietary Supplement: Preterm Formula
    Preterm formula is a type of infant formula designed for preterm infants. It is used when mother's own milk is not available or not in sufficient amount as the enteral feeding for preterm infants in hospitals that do not have donor human milk.
Study Arms  ICMJE
  • Active Comparator: Preterm Formula
    MM is always the first priority, when available. When MM is not available, or the available amounts do not fulfill the needs, infants in this group will receive preterm formula, as the supplementary diets following the standard feeding guidelines in the participating hospitals.
    Intervention: Dietary Supplement: Preterm Formula
  • Experimental: Bovine Colostrum
    MM is always the first priority, when available. When MM is not available, or the available amounts do not fulfill the needs, infants in this group will receive Bovine Colostrum (BC), as the supplementary diets. BC feeding follows the same guideline as the control group in terms of initiation time (within 24-48h of age) and volume (5-10 ml/kg) and advancing rate (5-20 ml/kg/d). BC intervention should not exceed postnatal day 14.
    Intervention: Dietary Supplement: Bovine Colostrum
Publications * Juhl SM, Ye X, Zhou P, Li Y, Iyore EO, Zhang L, Jiang P, van Goudoever JB, Greisen G, Sangild PT. Bovine Colostrum for Preterm Infants in the First Days of Life: A Randomized Controlled Pilot Trial. J Pediatr Gastroenterol Nutr. 2018 Mar;66(3):471-478. doi: 10.1097/MPG.0000000000001774.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 17, 2019)
350
Original Estimated Enrollment  ICMJE
 (submitted: March 14, 2017)
352
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Preterm infants with gestational age between 26+0 and 31+6 weeks
  • Delivered at participating hospitals or transferred from other hospitals within 24 h of age
  • Signed parental consent

Exclusion Criteria:

  • Major congenital anomalies or birth defects
  • Congenital infection defined as suspected TORCHES infections: Toxoplasmosis, Rubella, CMV, Herpes, Hepatitis, Coxcackie, Syphilis, Varicella Zoster, HIV, Parvo B19
  • Perinatal asphyxia with blood pH < 7.0 (umbilical or first neonatal)
  • Extremely small for gestational age (birth weight z-score ≤ - 3)
  • No realistic hope of immediate survival
  • Has received any formula feeding prior to randomization
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 2 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE China
Removed Location Countries Taiwan
 
Administrative Information
NCT Number  ICMJE NCT03085277
Other Study ID Numbers  ICMJE Precolos-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  ICMJE
Plan to Share IPD: No
Responsible Party Per Torp Sangild, Rigshospitalet, Denmark
Study Sponsor  ICMJE Per Torp Sangild
Collaborators  ICMJE
  • Sixth Affiliated Hospital, Sun Yat-sen University
  • Maternal and Child Health Hospital of Foshan
  • Shenzhen People's Hospital
  • Shenzhen Luohu Maternal and Child Health Hospital
  • Guangming District People's Hospital of Shenzhen
  • Longgang District Central Hospital of Shenzhen
  • Shenzhen Nanshan Maternity and Child Healthcare Hospital
  • Zhuhai Maternal and Child Health Care Hospital
  • Dongguan Women and Children's Hospital
Investigators  ICMJE
Study Chair: Per Sangild, PhD University of Copenhagen
PRS Account Rigshospitalet, Denmark
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP