Donor Milk vs. Formula in Extremely Low Birth Weight (ELBW) Infants

• ClinicalTrials.gov Identifier: NCT01534481
• Recruitment Status: Completed
• First Posted: February 16, 2012
• Results First Posted: February 6, 2023
• Last Update Posted: February 6, 2023
• Sponsor: NICHD Neonatal Research Network
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): NICHD Neonatal Research Network

Tracking Information

• First Submitted Date: February 13, 2012
• First Posted Date: February 16, 2012
• Results First Submitted Date: November 29, 2022
• Results First Posted Date: February 6, 2023
• Last Update Posted Date: February 6, 2023
• Actual Study Start Date: August 2012
• Actual Primary Completion Date: November 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 1, 2023)

Bayley Scales of Infant Development (BSID) Cognitive Composite Score [ Time Frame: At 22-26 months corrected age ]

Mean cognitive composite score (standardized mean 100, SD 15, range 54-145). Subjects who died prior to follow-up assigned the score of 54. (lower scores indicating greater impairment)

Original Primary Outcome Measures (submitted: February 13, 2012)

Neurodevelopmental Outcome [ Time Frame: 18-22 months corrected age ]

As measured by scores on Bayley Scales of Infant Development III (BSID III)

Current Secondary Outcome Measures (submitted: February 1, 2023)

• Total Deaths Before Discharge [ Time Frame: From day of randomization to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 1 year following birth ]
  Infant died before discharge home.
• Late Onset Sepsis (LOS) [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
  Number of infants diagnosed with LOS
• Necrotizing Enterocolitis (NEC) [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
  Number of infants diagnosed with NEC
• Death or Necrotizing Enterocolitis (NEC) [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
  A composite outcome that measures the occurrence of death or NEC
• Change in Weight-for-age Z-score During Study [ Time Frame: During Study Intervention, the time between study randomization and discontinuation of study protocol. Infants exited from the study protocol 1-2 weeks prior to anticipated hospital discharge or 120 days, whichever is sooner ]
  Weight-for-age Z-scores were calculated at both baseline (study initiation) and study end (within one week of last study data collected) based on Fenton growth curves (2013). This outcome represents the change in weight-for-age Z-score during the course of the study (i.e., the Z-score at baseline was subtracted from the Z-score at study end). A value of 0 represents that the infant's weight-for-age Z-score is the same at the beginning and the end of the study. Positive values indicate the increase in the infant's weight-for-age Z-score during the study; negative values indicate the decrease in the infant's weight-for-age Z-score during the study.
• Bayley Scales of Infant Development (BSID) Motor Composite Score [ Time Frame: At 22-26 months corrected age ]
  Mean motor composite score (standardized mean 100, range 44-155). Subjects who died prior to follow-up assigned the score of 44. (lower scores indicating greater impairment)
• Bayley Scales of Infant Development (BSID) Language Composite Score [ Time Frame: At 22-26 months corrected age ]
  Mean language composite score (standardized mean 100, range 46-155). Subjects who died prior to follow-up assigned the score of 46. (lower scores indicating greater impairment)
• Moderate to Severe Cerebral Palsy [ Time Frame: At 22-26 months corrected age ]
  Number of infants with moderate or severe grade of cerebral palsy
• Neurodevelopmental Impairment (NDI). [ Time Frame: At 22-26 months corrected age ]
  Number of infants with NDI. NDI is defined as any of the following: Gross Motor Function Classification System score greater than or equal to 2, Bayley III cognitive or motor score less than 85 (1 standard deviation), Vision Impairment or Hearing impairment
• Profound Impairment [ Time Frame: At 22-26 months corrected age ]
  Number of infants with profound impairment.
• Death or Neurodevelopmental Impairment (NDI) [ Time Frame: At 22-26 months corrected age ]
  A composite outcome that measures the occurrence of death through 22-26 months or NDI.

Original Secondary Outcome Measures (submitted: February 13, 2012)

• In Hospital Morbidities [ Time Frame: Up to one year ]
  These include:

  • Death
  • Late onset sepsis or meningitis
  • Length of TPN use
  • Length of initial hospital stay
  • Necrotizing enterocolitis
  • Bronchopulmonary dysplasia (BPD), defined as room air oxygen saturation of less than 90% at 36 weeks postmenstrual age using the NRN standard physiologic definition of BPD.
  • Necrotizing enterocolitis or death
  • BPD or death
• Growth outcomes [ Time Frame: 36 Weeks and 18-22 months corrected age ]
  In-Hospital growth parameters, including rate of weight gain, weight, length and head circumference at 36 weeks or discharge, whichever comes first. Weights will be obtained from hospital records weekly, length and head circumference will be measured bi-weekly by study personnel.
• Follow-up Outcomes [ Time Frame: 18-22 months corrected age ]
  • Number of hospital admissions between initial discharge and follow-up
  • Motor and Language scores on the BSID III
  • Cerebral Palsy
  • Neurodevelopmental Impairment (NDI), using current Follow-Up Study definition.
  • Profound Impairment, defined as BSID III Cognitive subscale score of 70
  • NDI or death
  • Profound Impairment or death

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Donor Milk vs. Formula in Extremely Low Birth Weight (ELBW) Infants
• Official Title: Neurodevelopmental Effects of Donor Human Milk vs. Preterm Formula in Extremely Low Birth Weight (ELBW) Infants
• Brief Summary: The Milk Trial seeks to determine the effect on neurodevelopmental outcomes at age 22-26 months of donor human milk as compared to preterm infant formula as the in-hospital diet for infants whose mothers choose not to provide breast milk or are able to provide only a minimal amount. Infants will be randomized to receive donor breast milk or formula during their hospital stay. Infant's will be followed until they reach 22-26 months of age.
• Detailed Description: There is strong evidence that maternal breast milk feedings in infancy confer multiple health benefits in the extremely preterm population (extremely low birth weight, ELBW, <1000 g). Studies suggest an IQ advantage of up to 8 points conferred by maternal milk feeding in this population. Rates of sepsis and necrotizing enterocolitis are also lower in human milk fed ELBW infants, and they experience shorter hospital stays and fewer re-hospitalizations in the first year of life. When mothers choose not to or are unable to provide milk, preterm formula is usually used. Recently, pasteurized donor human milk is available in some NICUs in the US as an alternative to preterm formula. Donor milk has not been well studied with regard to its safety and efficacy. It is unknown if donor human milk confers the same benefits as maternal milk with regard to neurodevelopmental and health outcomes. The proposed study will be the first US multicenter randomized trial of the health and developmental effects of donor milk as compared to preterm formula in ELBW infants receiving little or no maternal milk. Our long-term goal is to optimize neurodevelopmental and health outcomes for ELBW infants, maximizing their quality of life and societal functionality throughout their lives. If donor human milk has similar effects to maternal milk, the public health benefit of donor milk feedings in ELBW infants unable to receive maternal milk would be considerable.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Infant, Newborn
• Infant, Small for Gestational Age
• Infant, Extremely Low Birth Weight

Intervention

• Biological: Donor Milk
  Donor milk provided by the Human Milk Banking Association of North America
• Dietary Supplement: Preterm Formula
  Preterm Formula determined by center practice.

Study Arms

• Active Comparator: Donor Milk
  Donor milk provided by the Human Milk Banking Association of North America
  Intervention: Biological: Donor Milk
• Placebo Comparator: Preterm Formula
  Preterm formula determined by center practice
  Intervention: Dietary Supplement: Preterm Formula

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 16, 2019): 483
• Original Estimated Enrollment (submitted: February 13, 2012): 670
• Actual Study Completion Date: November 30, 2021
• Actual Primary Completion Date: November 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Gestational age less than 29 weeks.
• Admitted to the NICU at less than or equal to 72 hours of life
• Survived at least 12 hours

Exclusion Criteria:

• Chromosomal anomalies
• Cyanotic congenital heart disease
• Diagnosed intrauterine infection
• Other congenital disorders known to impair neurodevelopment
• NEC or IP prior to seeking consent
• Decision documented to limit intensive care therapies
• Congenital disorders that may affect feeding

Feeding Group Eligibility:

• Sole Diet Group: Infants will be eligible for the sole diet feeding protocol if the mother declines to provide breast milk for the baby.
• Supplemental Diet (minimal maternal milk) Group: Infants whose mothers initially choose to provide breast milk and begin pumping will be re-screened for eligibility at least weekly until the infant is 21 days old. If the mother stops expressing milk at any point prior to the infant's 21st day of life, her infant will be eligible for randomization. In addition, those whose mothers are providing less than 20% of the infant's dietary needs (averaged over past 5 days) when the infant reaches 21 days of age will be eligible for randomization at this point. No infant will be randomized after reaching 21 days.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 21 Days (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01534481
• Other Study ID Numbers: NICHD-NRN-0047; U10HD021364 ( U.S. NIH Grant/Contract ); U10HD040689 ( U.S. NIH Grant/Contract ); U10HD021385 ( U.S. NIH Grant/Contract ); U10HD027851 ( U.S. NIH Grant/Contract ); U10HD027853 ( U.S. NIH Grant/Contract ); U10HD027856 ( U.S. NIH Grant/Contract ); U10HD027904 ( U.S. NIH Grant/Contract ); U10HD027880 ( U.S. NIH Grant/Contract ); U10HD034216 ( U.S. NIH Grant/Contract ); U10HD021373 ( U.S. NIH Grant/Contract ); U10HD040492 ( U.S. NIH Grant/Contract ); U10HD053109 ( U.S. NIH Grant/Contract ); U10HD040461 ( U.S. NIH Grant/Contract ); U10HD068244 ( U.S. NIH Grant/Contract ); U10HD068263 ( U.S. NIH Grant/Contract ); U10HD068278 ( U.S. NIH Grant/Contract ); U10HD068284 ( U.S. NIH Grant/Contract ); U10HD036790 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov)

• Current Responsible Party: NICHD Neonatal Research Network
• Original Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Current Study Sponsor: NICHD Neonatal Research Network
• Original Study Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Study Director: Tarah Colaizy, MD, MPH; University of Iowa
• Principal Investigator: Michele C Walsh, MD; Case Western Reserve University, Rainbow Babies and Children's Hospital
• Principal Investigator: Seetha Shankaran, MD; Wayne State University
• Principal Investigator: Abbot R Laptook, MD; Brown University, Women & Infants Hospital of Rhode Island
• Principal Investigator: C. Michael Cotten, MD; Duke University
• Principal Investigator: David Carlton, MD; Emory University
• Principal Investigator: Greg Sokol, MD; Indiana University
• Principal Investigator: Abhik Das, PhD; RTI International
• Principal Investigator: Krisa P Van Meurs, MD; Stanford University
• Principal Investigator: Waldemar A Carlo, MD; University of Alabama at Birmingham
• Principal Investigator: Kristi L Watterberg, MD; University of New Mexico
• Principal Investigator: Myra Wyckoff, MD; University of Texas, Southwestern Medical Center at Dallas
• Principal Investigator: Jon Tyson, MD, MPH; The University of Texas Health Science Center, Houston
• Principal Investigator: Sara DeMauro, MD; University of Pennsylvania
• Principal Investigator: Carl T D'Angio, MD; University of Rochester
• Principal Investigator: Pablo J Sanchez, MD; Research Institute at Nationwide Children's Hospital
• Principal Investigator: William Truog, MD; Children's Mercy Hospital Kansas City

• PRS Account: NICHD Neonatal Research Network
• Verification Date: January 2023