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Bovine Colostrum for Preterm Newborns (PreColos-RCT)

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ClinicalTrials.gov Identifier: NCT03085277
Recruitment Status : Recruiting
First Posted : March 21, 2017
Last Update Posted : January 23, 2019
Sponsor:
Collaborators:
Sixth Affiliated Hospital, Sun Yat-sen University
Maternal and Child Health Hospital of Foshan
China Medical University Hospital
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

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.

Condition or disease Intervention/treatment Phase
Enteral Feeding Intolerance Necrotizing Enterocolitis Late-Onset Neonatal Sepsis Dietary Supplement: Bovine Colostrum Dietary Supplement: Preterm Formula Not Applicable

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 350 participants
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
Official Title: Bovine Colostrum Versus Preterm Formula as the First Supplemental Nutrition for Very Preterm Infants, a Randomized, Controlled Trial
Actual Study Start Date : July 1, 2017
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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.

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.
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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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


  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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.


Other Outcome Measures:
  1. 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

  2. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 2 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03085277


Contacts
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Contact: Per Sangild, PhD +45 35 33 26 98 pts@sund.ku.dk
Contact: Yanqi Li, PhD +45 35331099 yli@sund.ku.dk

Locations
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China, Guangdong
Foshan Maternal and Child Health Hospital Not yet recruiting
Foshan, Guangdong, China
Contact: Yiheng Dai       daiyiheng@163.com   
Contact: Xiaoyan Gao       gxy270000@sina.com   
Principal Investigator: Yiheng Dai         
Sub-Investigator: Xiaoyan Gao         
The First Affiliated Hospital of Jinan Medical University Not yet recruiting
Guangzhou, Guangdong, China
Contact: Guosheng Liu       tlgs@jnu.edu.cn   
Contact: Wenchao Chen       follen@163.com   
Principal Investigator: Guosheng Liu         
Sub-Investigator: Wenchao Chen         
Sub-Investigator: Xia Wu         
The Sixth Affiliated Hospital of Sun Yat-sen University Recruiting
Guangzhou, Guangdong, China
Contact: Hu Hao       freehaotiger@126.com   
Contact: Fei Ma       maf.0@163.com   
Principal Investigator: Hu Hao         
Sub-Investigator: Mengxian Liu         
Longgang District Central Hospital of Shenzhen Not yet recruiting
Shenzhen, Guangdong, China
Contact: Huixian Qiu       szlgqhx@126.com   
Contact: Xunbin Huang       hxb_2710@163.com   
Principal Investigator: Huixian Qiu         
Sub-Investigator: Xunbin Huang         
Sub-Investigator: Shujuan Zeng         
Shenzhen Guangming People's Hospital Not yet recruiting
Shenzhen, Guangdong, China
Contact: Zhenzhi Ye       zhenzhiye2@163.com   
Contact: Xiaoli Chen       fmcxl213@126.com   
Principal Investigator: Zhenzhi Ye         
Sub-Investigator: Xiaoli Chen         
Shenzhen Luohu Maternal and Child Health Hospital Recruiting
Shenzhen, Guangdong, China
Contact: Yuefeng Li       liyuefeng111@sina.com   
Contact: Xuelei Gong       gongxuelei1987@163.com   
Principal Investigator: Yuefeng Li         
Sub-Investigator: Xuelei Gong         
Shenzhen Nanshan Maternal and Child Health Hospital Recruiting
Shenzhen, Guangdong, China
Contact: Luanying Tian       1782701141@qq.com   
Contact: Xiujuan Wu       wuxiujuan1978@126.com   
Principal Investigator: Luanying Tian         
Sub-Investigator: Xiujuan Wu         
Shenzhen People's Hospital Recruiting
Shenzhen, Guangdong, China
Contact: Benqing Wu    +86 139 0243 6593    wubenqing783@126.com   
Contact: Lu Ding    +86 13922851709    459208691@qq.com   
Principal Investigator: Benqing Wu         
Sub-Investigator: Ding Lu         
Sub-Investigator: Jinzhen Su         
Taiwan
China Medical University Children Hospital Not yet recruiting
Taichung, Taiwan
Contact: Hung-Chih Lin       d0373.cmuh@gmail.com   
Contact: Hsiang-Yu Lin       hylin.neo@gmail.com   
Principal Investigator: Hung-Chih Lin         
Sub-Investigator: Hsiang-Yu Lin         
Sponsors and Collaborators
Per Torp Sangild
Sixth Affiliated Hospital, Sun Yat-sen University
Maternal and Child Health Hospital of Foshan
China Medical University Hospital
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
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Study Chair: Per Sangild, PhD University of Copenhagen

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Per Torp Sangild, Professor, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03085277     History of Changes
Other Study ID Numbers: Precolos-RCT
First Posted: March 21, 2017    Key Record Dates
Last Update Posted: January 23, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
Bovine colostrum
Preterm formula
Very preterm infants
Enteral feeding

Additional relevant MeSH terms:
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Premature Birth
Enterocolitis
Enterocolitis, Necrotizing
Neonatal Sepsis
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Sepsis
Infection
Infant, Newborn, Diseases
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes